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Sample records for human muscle metabolism

  1. Regulation of Metabolic Signaling in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Albers, Peter Hjorth

    enzymes. Skeletal muscle consists of thousands of muscle fibers. These fibers can roughly be classified into type I and type II muscle fibers. The overall aim of this PhD thesis was to investigate the effect of insulin and exercise on human muscle fiber type specific metabolic signaling. The importance...

  2. IL-6 selectively stimulates fat metabolism in human skeletal muscle

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    Wolsk, Emil; Mygind, Helene; Grøndahl, Thomas S

    2010-01-01

    Interleukin (IL)-6 is chronically elevated in type 2 diabetes but also during exercise. However, the exact metabolic role, and hence the physiological significance, has not been elucidated. The objective of this study was to investigate the in vivo effect of recombinant human (rh) IL-6 on human fat...... and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ∼40 and ∼1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed...... before, during, and 2 h after cessation of the infusion. Glucose metabolism was unaffected by rhIL-6. In contrast, rhIL-6 increased systemic fatty acid oxidation approximately twofold after 60 min, and it remained elevated even 2 h after the infusion. The increase in oxidation was followed by an increase...

  3. IL-6 selectively stimulates fat metabolism in human skeletal muscle

    DEFF Research Database (Denmark)

    Wolsk, Emil; Mygind, Helene; Grøndahl, Thomas S

    2010-01-01

    Interleukin (IL)-6 is chronically elevated in type 2 diabetes but also during exercise. However, the exact metabolic role, and hence the physiological significance, has not been elucidated. The objective of this study was to investigate the in vivo effect of recombinant human (rh) IL-6 on human fat...... and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ~40 and ~1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed...... before, during, and 2 h after cessation of the infusion. Glucose metabolism was unaffected by rhIL-6. In contrast, rhIL-6 increased systemic fatty acid oxidation approximately twofold after 60 min, and it remained elevated even 2 h after the infusion. The increase in oxidation was followed by an increase...

  4. Metabolic control of muscle blood flow during exercise in humans

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    Boushel, Robert Christopher

    2003-01-01

    to exert control of muscle vasodilation. Adenosine, nitric oxide (NO), prostacyclin (PGI2), and endothelial-derived hyperpolarization factor (EDHF) are possible mediators of muscle vasodilation during exercise. In humans, adenosine has been shown to contribute to functional hyperemia as blood flow...... that combined blockade of NOS and PGI2, and NOS and cytochrome P450, both attenuate exercise-induced hyperemia in humans. Combined vasodilator blockade studies offer the potential to uncover important interactions and compensatory vasodilator responses. The signaling pathways that link metabolic events evoked...

  5. Effect of repeated forearm muscle cooling on the adaptation of skeletal muscle metabolism in humans

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    Wakabayashi, Hitoshi; Nishimura, Takayuki; Wijayanto, Titis; Watanuki, Shigeki; Tochihara, Yutaka

    2017-07-01

    This study aimed to investigate the effect of repeated cooling of forearm muscle on adaptation in skeletal muscle metabolism. It is hypothesized that repeated decreases of muscle temperature would increase the oxygen consumption in hypothermic skeletal muscle. Sixteen healthy males participated in this study. Their right forearm muscles were locally cooled to 25 °C by cooling pads attached to the skin. This local cooling was repeated eight times on separate days for eight participants (experimental group), whereas eight controls received no cold exposure. To evaluate adaptation in skeletal muscle metabolism, a local cooling test was conducted before and after the repeated cooling period. Change in oxy-hemoglobin content in the flexor digitorum at rest and during a 25-s isometric handgrip (10% maximal voluntary construction) was measured using near-infrared spectroscopy at every 2 °C reduction in forearm muscle temperature. The arterial blood flow was occluded for 15 s by upper arm cuff inflation at rest and during the isometric handgrip. The oxygen consumption in the flexor digitorum muscle was evaluated by a slope of the oxy-hemoglobin change during the arterial occlusion. In the experimental group, resting oxygen consumption in skeletal muscle did not show any difference between pre- and post-intervention, whereas muscle oxygen consumption during the isometric handgrip was significantly higher in post-intervention than in pre-test from thermoneutral baseline to 31 °C muscle temperature ( P < 0.05). This result indicated that repeated local muscle cooling might facilitate oxidative metabolism in the skeletal muscle. In summary, skeletal muscle metabolism during submaximal isometric handgrip was facilitated after repeated local muscle cooling.

  6. IMP metabolism in human skeletal muscle after exhaustive exercise

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    Tullson, P. C.; Bangsbo, Jens; Hellsten, Ylva

    1995-01-01

    This study addressed whether AMP deaminase (AMPD)myosin binding occurs with deamination during intense exercise in humans and the extent of purine loss from muscle during the initial minutes of recovery. Male subjects performed cycle exercise (265 +/- 2 W for 4.39 +/- 0.04 min) to stimulate muscle...... inosine 5'-monophosphate (IMP) formation. After exercise, blood flow to one leg was occluded. Muscle biopsies (vastus lateralis) were taken before and 3.6 +/- 0.2 min after exercise from the occluded leg and 0.7 +/- 0.0, 1.1 +/- 0.0, and 2.9 +/- 0.1 min postexercise in the nonoccluded leg. Exercise...... activated AMPD; at exhaustion IMP was 3.5 +/- 0.4 mmol/kg dry muscle. Before exercise, 16.0 +/- 1.6% of AMPD cosedimented with the myosin fraction; the extent of AMPD:myosin binding was unchanged by exercise. Inosine content increased about threefold during exercise and twofold more during recovery; by 2...

  7. Exercise and training effects on ceramide metabolism in human skeletal muscle

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    Helge, Jørn Wulff; Dobrzyn, Agnieszka; Saltin, Bengt

    2004-01-01

    In rat skeletal muscle prolonged exercise affects the content and composition of ceramides, but in human skeletal muscle no data are available on this compound. Our aim was to examine the content of ceramide- and sphingomyelin fatty acids and neutral, Mg(2+)-dependent sphingomyelinase activity...... in skeletal muscle in untrained and trained subjects before and after prolonged exercise. Healthy male subjects were recruited into an untrained (n = 8, VO2,max 3.8 +/- 0.2 1 min1) and a trained (n = 8, Vo2,max 5.1 +/- 0.1 1 min2) group. Before and after a 3-h exercise bout (58 +/- 1% VO2,max) a muscle biopsy......). In conclusion, we have reported, for the first time, the values for ceramide fatty acid content and neutral, Mg2(+)-dependent sphingomyelinase activity in human skeletal muscle. The results indicate that acute prolonged exercise affects ceramide metabolism in human skeletal muscle both in untrained...

  8. Plasticity in mitochondrial cristae density allows metabolic capacity modulation in human skeletal muscle

    DEFF Research Database (Denmark)

    Nielsen, Joachim; Gejl, Kasper D; Hey-Mogensen, Martin

    2017-01-01

    , in human skeletal muscle, contrary to the current view, the mitochondrial cristae density is not constant, but exhibits plasticity with long-term endurance training. Furthermore, we show that frequently recruited mitochondria-enriched fibres have significantly increased cristae density and that, at whole......Mitochondrial energy production involves the movement of protons down a large electrochemical gradient through ATP synthase located on the folded inner membrane, known as cristae. In mammalian skeletal muscle, the density of cristae in mitochondria is thought to be constant. However, recent......-body level, muscle mitochondrial cristae density is a better predictor of maximal oxygen uptake rate than muscle mitochondrial volume. Our findings establish elevating mitochondrial cristae density as a regulatory mechanism for increasing metabolic power in human skeletal muscle. We propose...

  9. Treatment of human muscle cells with popular dietary supplements increase mitochondrial function and metabolic rate

    Directory of Open Access Journals (Sweden)

    Vaughan Roger A

    2012-11-01

    Full Text Available Abstract Background Obesity is a common pathology with increasing incidence, and is associated with increased mortality and healthcare costs. Several treatment options for obesity are currently available ranging from behavioral modifications to pharmaceutical agents. Many popular dietary supplements claim to enhance weight loss by acting as metabolic stimulators, however direct tests of their effect on metabolism have not been performed. Purpose This work identified the effects popular dietary supplements on metabolic rate and mitochondrial biosynthesis in human skeletal muscle cells. Methods Human rhabdomyosarcoma cells were treated with popular dietary supplements at varied doses for 24 hours. Peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α, an important stimulator of mitochondrial biosynthesis, was quantified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR. Mitochondrial content was measured using flow cytometry confirmed with confocal microscopy. Glycolytic metabolism was quantified by measuring extracellular acidification rate (ECAR and oxidative metabolism was quantified by measuring oxygen consumption rate (OCR. Total relative metabolism was quantified using WST-1 end point assay. Results Treatment of human rhabdomyosarcoma cells with dietary supplements OxyElite Pro (OEP or Cellucore HD (CHD induced PGC-1α leading to significantly increased mitochondrial content. Glycolytic and oxidative capacities were also significantly increased following treatment with OEP or CHD. Conclusion This is the first work to identify metabolic adaptations in muscle cells following treatment with popular dietary supplements including enhanced mitochondrial biosynthesis, and glycolytic, oxidative and total metabolism.

  10. Substrate availability and transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise

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    Pilegaard, Henriette; Osada, Takuya; Andersen, Lisbeth Tingsted

    2005-01-01

    providing LC during recovery elicited a sustained/enhanced increase in activation of these genes through 8 to 24 hours of recovery. These findings provide evidence that factors associated with substrate availability and/or cellular metabolic recovery (eg, muscle glycogen restoration) influence......In skeletal muscle of humans, transcription of several metabolic genes is transiently induced during recovery from exercise when no food is consumed. To determine the potential influence of substrate availability on the transcriptional regulation of metabolic genes during recovery from exercise, 9...... male subjects (aged 22-27) completed 75 minutes of cycling exercise at 75% V¿o2max on 2 occasions, consuming either a high-carbohydrate (HC) or low-carbohydrate (LC) diet during the subsequent 24 hours of recovery. Nuclei were isolated and tissue frozen from vastus lateralis muscle biopsies obtained...

  11. Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans.

    Science.gov (United States)

    Huh, J Y; Dincer, F; Mesfum, E; Mantzoros, C S

    2014-12-01

    Irisin is a recently identified exercise-induced myokine suggested to induce browning of white adipocytes. Deficiency of myostatin, and thus stimulation of muscle growth, has also been reported to induce irisin and its precursor FNDC5 expression in muscle and drive the browning of white adipocytes in mice, implying that irisin may be related to muscle growth in addition to its beneficial effects in adipocytes. In humans, the effect of irisin in muscle hypertrophy as well as adipocyte metabolism has not been fully investigated. Primary cultured human myocytes/adipocytes and 3T3-L1 cells were used to examine irisin-regulated gene/protein expression. Lipid accumulation, ATP content, glycolysis, lipolysis and metabolite profile were measured in control and irisin-treated (10 and 50 nM) adipocytes. In human myocytes, FNDC5 mRNA and irisin secretion were increased during myogenic differentiation, along with PGC1α and myogenin expression. Irisin treatment significantly increased insulin-like growth factor 1 and decreased myostatin gene expression through ERK pathway. PGC1α4, a newly discovered PGC1α isoform specifically related to muscle hypertrophy, was also upregulated. In human adipocytes, irisin induced uncoupling protein 1 and consequently increased adipocyte energy expenditure, expression of metabolic enzymes and metabolite intermediates, resulting in inhibition of lipid accumulation. Irisin and FNDC5 treatment also reduced preadipocyte differentiation, suggesting an additional mechanism in suppressing fat mass. These results suggest that irisin/FNDC5 has a pleiotropic role in muscle and improvement of adipocyte metabolism in humans.

  12. Physical activity is associated with retained muscle metabolism in human myotubes challenged with palmitate

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    Green, C J; Bunprajun, T; Pedersen, B K

    2013-01-01

      The aim of this study was to investigate whether physical activity is associated with preserved muscle metabolism in human myotubes challenged with saturated fatty acids. Human muscle satellite cells were isolated from sedentary or active individuals and differentiated into myocytes in culture....... Metabolic differences were then investigated in the basal state or after chronic palmitate treatment. At basal, myocytes from sedentary individuals exhibited higher CD36 and HSP70 protein expression as well as elevated phosphorylation of c-Jun NH2-terminal kinase (JNK) and insulin receptor substrate 1 (IRS1......) serine(307) compared to myocytes from active individuals. Despite equal lipid accumulation following palmitate treatment, myocytes from sedentary individuals exhibited delayed acetyl coenzyme A carboxylase phosphorylation compared to the active group. Myocytes from sedentary individuals had significantly...

  13. TCA cycle rewiring fosters metabolic adaptation to oxygen restriction in skeletal muscle from rodents and humans.

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    Capitanio, Daniele; Fania, Chiara; Torretta, Enrica; Viganò, Agnese; Moriggi, Manuela; Bravatà, Valentina; Caretti, Anna; Levett, Denny Z H; Grocott, Michael P W; Samaja, Michele; Cerretelli, Paolo; Gelfi, Cecilia

    2017-08-29

    In mammals, hypoxic stress management is under the control of the Hypoxia Inducible Factors, whose activity depends on the stabilization of their labile α subunit. In particular, the skeletal muscle appears to be able to react to changes in substrates and O2 delivery by tuning its metabolism. The present study provides a comprehensive overview of skeletal muscle metabolic adaptation to hypoxia in mice and in human subjects exposed for 7/9 and 19 days to high altitude levels. The investigation was carried out combining proteomics, qRT-PCR mRNA transcripts analysis, and enzyme activities assessment in rodents, and protein detection by antigen antibody reactions in humans and rodents. Results indicate that the skeletal muscle react to a decreased O2 delivery by rewiring the TCA cycle. The first TCA rewiring occurs in mice in 2-day hypoxia and is mediated by cytosolic malate whereas in 10-day hypoxia the rewiring is mediated by Idh1 and Fasn, supported by glutamine and HIF-2α increments. The combination of these specific anaplerotic steps can support energy demand despite HIFs degradation. These results were confirmed in human subjects, demonstrating that the TCA double rewiring represents an essential factor for the maintenance of muscle homeostasis during adaptation to hypoxia.

  14. Unusual metabolic characteristics in skeletal muscles of transgenic rabbits for human lipoprotein lipase

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    Viglietta Céline

    2004-12-01

    Full Text Available Abstract Background The lipoprotein lipase (LPL hydrolyses circulating triacylglycerol-rich lipoproteins. Thereby, LPL acts as a metabolic gate-keeper for fatty acids partitioning between adipose tissue for storage and skeletal muscle primarily for energy use. Transgenic mice that markedly over-express LPL exclusively in muscle, show increases not only in LPL activity, but also in oxidative enzyme activities and in number of mitochondria, together with an impaired glucose tolerance. However, the role of LPL in intracellular nutrient pathways remains uncertain. To examine differences in muscle nutrient uptake and fatty acid oxidative pattern, transgenic rabbits harboring a DNA fragment of the human LPL gene (hLPL and their wild-type littermates were compared for two muscles of different metabolic type, and for perirenal fat. Results Analyses of skeletal muscles and adipose tissue showed the expression of the hLPL DNA fragment in tissues of the hLPL group only. Unexpectedly, the activity level of LPL in both tissues was similar in the two groups. Nevertheless, mitochondrial fatty acid oxidation rate, measured ex vivo using [1-14C]oleate as substrate, was lower in hLPL rabbits than in wild-type rabbits for the two muscles under study. Both insulin-sensitive glucose transporter GLUT4 and muscle fatty acid binding protein (H-FABP contents were higher in hLPL rabbits than in wild-type littermates for the pure oxidative semimembranosus proprius muscle, but differences between groups did not reach significance when considering the fast-twitch glycolytic longissimus muscle. Variations in both glucose uptake potential, intra-cytoplasmic binding of fatty acids, and lipid oxidation rate observed in hLPL rabbits compared with their wild-type littermates, were not followed by any modifications in tissue lipid content, body fat, and plasma levels in energy-yielding metabolites. Conclusions Expression of intracellular binding proteins for both fatty acids and

  15. Metabolic Diseases of Muscle

    Science.gov (United States)

    ... ing fuel, and no energy is produced for muscle function. 4 Metabolic Diseases of Muscle • ©2011 MDA A ... This slowly progressive disorder causes cardiac disease and muscle weakness in the hips, shoulders, and upper arms and legs. The neck and ...

  16. Linking skeletal muscle blood flow and metabolism to the limits of human performance.

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    Boushel, Robert

    2017-01-01

    Over the last 50 years, Bengt Saltin's contributions to our understanding of physiology of the circulation, the matching of the circulation to muscle metabolism, and the underlying mechanisms that set the limits for exercise performance were enormous. His research addressed the key questions in the field using sophisticated experimental methods including field expeditions. From the Dallas Bedrest Study to the 1-leg knee model to the physiology of lifelong training, his prodigious body of work was foundational in the field of exercise physiology and his leadership propelled integrative human physiology into the mainstream of biological sciences.

  17. Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle

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    Kaestner Klaus H

    2007-10-01

    Full Text Available Abstract Background Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype. Methods To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function. Results Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens. Conclusion The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of

  18. Human skeletal muscle fatty acid and glycerol metabolism during rest, exercise and recovery

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    Van Hall, Gerrit; Sacchetti, M; Rådegran, G

    2002-01-01

    glycerol uptake was observed, which was substantially higher during exercise. Total body skeletal muscle FA and glycerol uptake/release was estimated to account for 18-25 % of whole body R(d) or R(a). In conclusion: (1) skeletal muscle FA and glycerol metabolism, using the leg arterial-venous difference...

  19. Quantitative analysis of energy metabolism in human muscle using SLOOP {sup 31}P-MR-spectroscopy

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    Beer, M.; Koestler, H.; Buchner, S.; Sandstede, J.; Hahn, D. [Wuerzburg Univ. (Germany). Inst. fuer Roentgendiagnostik; Schneider, C.; Toyka, K.V. [Neurologische Klinik und Poliklinik der Univ. Wuerzburg (Germany)

    2002-05-01

    Objective: Energy metabolism is vital for regular muscle function. In humans, in vivo analysis using {sup 31}P-MR-spectroscopy (MRS) is mostly restricted to semiquantitative parameters due to technical demands. We applied spatial localization with optimal pointspread function (SLOOP) for quantification in human skeletal and cardiac muscle. Subjects/Methods: 10 healthy volunteers and 4 patients with myotonic dystrophy type 1 were examined using a 1.5 T system (Magnetom VISION) and chemical shift imaging (CSI) for data collection. Concentrations of PCr, ATP and P{sub i} as well as PCr/ATP ratios were calculated by SLOOP. Results: Concentrations of PCr, ATP and P{sub i} were 29.9{+-}3.4, 7.1{+-}0.9 and 5.7{+-}1.2 [mmol/kg] in normal skeletal muscle, corresponding to previously published studies. Two of the patients with a duration of disease longer than 10 years and a pronounced muscle weakness showed a significant decrease of PCr and ATP in skeletal muscle below 10 and 5 mmol/kg. One of these patients had an additional reduction of PCr in cardiac muscle. (orig.) [German] Ziel: Voraussetzung fuer eine regulaere Muskelfunktion ist ein intakter Energiestoffwechsel. Beim Menschen beschraenkten sich bisherige Untersuchungen mittels der {sup 31}P-MR-Spektroskopie (MRS), welche eine In-Vivo-Analyse erlaubt, jedoch zumeist auf die Analyse semiquantitativer Parameter. Wir verwendeten Spatial Localization with Optimal Pointspread Function (SLOOP), um den Stoffwechsel des Skelettmuskels wie des Herzens zu quantifizieren. Patienten/Methoden: 10 Probanden und 4 Patienten mit myotoner Dystrophie Typ 1 wurden an einem 1.5-T-System (Magnetom VISION) mittels der chemical shift imaging (CSI)-Technik untersucht. Die Berechnung der Konzentrationen von PCr, ATP und P{sub 1} sowie des PCr/ATP Verhaeltnisses erfolgte mittels SLOOP. Ergebnisse: Im Skelettmuskel gesunder Probanden betrugen die Absolutkonzentrationen fuer PCr, ATP und P{sub i} 29,9{+-}3.4, 7,1{+-}0,9 und 5,7{+-}1,2 [mmol

  20. The mRNA expression profile of metabolic genes relative to MHC isoform pattern in human skeletal muscles

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    Plomgaard, Peter; Penkowa, Milena; Leick, Lotte

    2006-01-01

    The metabolic profile of rodent muscle is generally reflected in the myosin heavy chain (MHC) fiber-type composition. The present study was conducted to test the hypothesis that metabolic gene expression is not tightly coupled with MHC fiber-type composition for all genes in human skeletal muscle...... was more than twofold higher in soleus and vastus than in triceps. Contrary, phosphofructokinase and total lactate dehydrogenase (LDH) activity was approximately three- and twofold higher in triceps than in both soleus and vastus. Expression of metabolic genes was assessed by determining the mRNA content...... of a broad range of metabolic genes. The triceps muscle had two- to fivefold higher MHC IIa, phosphofructokinase, and LDH A mRNA content and two- to fourfold lower MHC I, lipoprotein lipase, CD36, hormone-sensitive lipase, and LDH B and hexokinase II mRNA than vastus lateralis or soleus. Interestingly...

  1. Intramuscular fatty acid metabolism in contracting and non-contracting human skeletal muscle

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    Sacchetti, M; Saltin, B; Osada, T

    2002-01-01

    The present study was undertaken to investigate the fate of blood-borne non-esterified fatty acids (NEFA) entering contracting and non-contracting knee extensor muscles of healthy young individuals. [U-(13)C]-palmitate was infused into a forearm vein during 5 h of one-legged knee extensor exercis...... and degraded and that the metabolic fate of plasma NEFA entering the muscle is influenced by muscle contraction, so that a higher proportion is directed towards oxidation at the expense of storage in mTAG....

  2. Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans

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    Fisher, James P; Seifert, Thomas; Hartwich, Doreen

    2010-01-01

    Isolated activation of metabolically sensitive skeletal muscle afferents (muscle metaboreflex) using post-exercise ischaemia (PEI) following handgrip partially maintains exercise-induced increases in arterial blood pressure (BP) and muscle sympathetic nerve activity (SNA), while heart rate (HR...... of cardiac parasympathetic reactivation on heart rate....... moderate (PEI-M) and high (PEI-H) intensity isometric handgrip performed at 25% and 40% maximum voluntary contraction, under control (no drug), parasympathetic blockade (glycopyrrolate) and beta-adrenergic blockade (metoprolol or propranalol) conditions, while beat-to-beat HR and BP were continuously...

  3. Muscle metabolism from near infrared spectroscopy during rhythmic handgrip in humans

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    Boushel, Robert Christopher; Pott, F; Madsen, P

    1998-01-01

    The rate of metabolism in forearm flexor muscles (MO2) was derived from near-infrared spectroscopy (NIRS-O2) during ischaemia at rest rhythmic handgrip at 15% and 30% of maximal voluntary contraction (MVC), post-exercise muscle ischaemia (PEMI), and recovery in seven subjects. The MO2 was compared...... with forearm oxygen uptake (VO2) [flow x (oxygen saturation in arnterial blood-oxygen saturation in venous blood, SaO2 - SvO2)], and with the 31P-magnetic resonance spectroscopy-determined ratio of inorganic phosphate to phosphocreatine (P(I):PCr). During ischaemia at rest, the fall in NIRS-O2 was more....... To conclude, NIRS-O2 of forearm flexor muscles closely reflected the exercise intensity and the metabolic rate determined by magnetic resonance spectroscopy but not that rate derived from flow and the arterio-venous oxygen difference....

  4. Bed rest reduces metabolic protein content and abolishes exercise-induced mRNA responses in human skeletal muscle

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    Jørgensen, Stine Ringholm; Biensø, Rasmus S; Kiilerich, Kristian

    2011-01-01

    Background: The aim was to test the hypothesis that one week of bed rest will reduce mitochondrial number and expression and activity of oxidative proteins in human skeletal muscle, but that exercise-induced intracellular signaling as well as mRNA and microRNA (miR) responses are maintained after...... kinase phosphorylation, peroxisome proliferator activated receptor ¿ coactivator-1a and VEGF mRNA content in skeletal muscle before bed rest, but the responses were abolished after bed rest. Conclusion: The present findings indicate that only 7 days of physical inactivity reduce skeletal muscle metabolic...... capacity as well as abolish exercise-induced adaptive gene responses likely reflecting the interference with the ability of skeletal muscle to adapt to exercise....

  5. Post-exercise adipose tissue and skeletal muscle lipid metabolism in humans

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    Mulla, N A; Simonsen, L; Bülow, J

    2000-01-01

    One purpose of the present experiments was to examine whether the relative workload or the absolute work performed is the major determinant of the lipid mobilization from adipose tissue during exercise. A second purpose was to determine the co-ordination of skeletal muscle and adipose tissue lipid......, a subcutaneous abdominal vein and a femoral vein. Adipose tissue metabolism and skeletal muscle (leg) metabolism were measured using Fick's principle. The results show that the lipolytic rate in adipose tissue during exercise was the same in each experiment. Post-exercise, there was a very fast decrease...... adipose tissue during exercise is the same whether the relative workload is 40% or 60% of maximum. Post-exercise, there is a substantial lipid mobilization from adipose tissue and only a small fraction of this is taken up in the lower extremities. This leaves a substantial amount of NEFAs for either NEFA...

  6. Chronic oral ingestion of l-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans

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    Wall, Benjamin T; Stephens, Francis B; Constantin-Teodosiu, Dumitru; Marimuthu, Kanagaraj; Macdonald, Ian A; Greenhaff, Paul L

    2011-01-01

    We have previously shown that insulin increases muscle total carnitine (TC) content during acute i.v. l-carnitine infusion. Here we determined the effects of chronic l-carnitine and carbohydrate (CHO; to elevate serum insulin) ingestion on muscle TC content and exercise metabolism and performance in humans. On three visits, each separated by 12 weeks, 14 healthy male volunteers (age 25.9 ± 2.1 years, BMI 23.0 ± 0.8 kg m−2) performed an exercise test comprising 30 min cycling at 50%, 30 min at 80%, then a 30 min work output performance trial. Muscle biopsies were obtained at rest and after exercise at 50% and 80% on each occasion. Following visit one, volunteers ingested either 80 g of CHO (Control) or 2 g of l-carnitine-l-tartrate and 80 g of CHO (Carnitine) twice daily for 24 weeks in a randomised, double blind manner. All significant effects reported occurred after 24 weeks. Muscle TC increased from basal by 21% in Carnitine (P < 0.05), and was unchanged in Control. At 50%, the Carnitine group utilised 55% less muscle glycogen compared to Control (P < 0.05) and 31% less pyruvate dehydrogenase complex (PDC) activation compared to before supplementation (P < 0.05). Conversely, at 80%, muscle PDC activation was 38% higher (P < 0.05), acetylcarnitine content showed a trend to be 16% greater (P < 0.10), muscle lactate content was 44% lower (P < 0.05) and the muscle PCr/ATP ratio was better maintained (P < 0.05) in Carnitine compared to Control. The Carnitine group increased work output 11% from baseline in the performance trial, while Control showed no change. This is the first demonstration that human muscle TC can be increased by dietary means and results in muscle glycogen sparing during low intensity exercise (consistent with an increase in lipid utilisation) and a better matching of glycolytic, PDC and mitochondrial flux during high intensity exercise, thereby reducing muscle anaerobic ATP production. Furthermore, these changes were associated with an

  7. Remodeling of oxidative energy metabolism by galactose improves glucose handling and metabolic switching in human skeletal muscle cells.

    Directory of Open Access Journals (Sweden)

    Eili Tranheim Kase

    Full Text Available Cultured human myotubes have a low mitochondrial oxidative potential. This study aims to remodel energy metabolism in myotubes by replacing glucose with galactose during growth and differentiation to ultimately examine the consequences for fatty acid and glucose metabolism. Exposure to galactose showed an increased [(14C]oleic acid oxidation, whereas cellular uptake of oleic acid uptake was unchanged. On the other hand, both cellular uptake and oxidation of [(14C]glucose increased in myotubes exposed to galactose. In the presence of the mitochondrial uncoupler carbonylcyanide p-trifluormethoxy-phenylhydrazone (FCCP the reserve capacity for glucose oxidation was increased in cells grown with galactose. Staining and live imaging of the cells showed that myotubes exposed to galactose had a significant increase in mitochondrial and neutral lipid content. Suppressibility of fatty acid oxidation by acute addition of glucose was increased compared to cells grown in presence of glucose. In summary, we show that cells grown in galactose were more oxidative, had increased oxidative capacity and higher mitochondrial content, and showed an increased glucose handling. Interestingly, cells exposed to galactose showed an increased suppressibility of fatty acid metabolism. Thus, galactose improved glucose metabolism and metabolic switching of myotubes, representing a cell model that may be valuable for metabolic studies related to insulin resistance and disorders involving mitochondrial impairments.

  8. Low expression of IL-18 and IL-18 receptor in human skeletal muscle is associated with systemic and intramuscular lipid metabolism-Role of HIV lipodystrophy

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    Lindegaard, Birgitte; Hvid, Thine; Wolsk Mygind, Helene

    2018-01-01

    -18 mRNA is expressed in human skeletal muscle but a role for IL-18 in muscle has not been identified. Patients with HIV-infection and lipodystrophy (LD) are characterized by lipid and glucose disturbances and increased levels of circulating IL-18. We hypothesized that skeletal muscle IL-18 and IL-18......INTRODUCTION: Interleukin (IL)-18 is involved in regulation of lipid and glucose metabolism. Mice lacking whole-body IL-18 signalling are prone to develop weight gain and insulin resistance, a phenotype which is associated with impaired fat oxidation and ectopic skeletal muscle lipid deposition. IL...... triglycerides (Rp = -0.73, plipid metabolism and hypertriglyceridemia....

  9. A PGC-1α- and muscle fibre type-related decrease in markers of mitochondrial oxidative metabolism in skeletal muscle of humans with inherited insulin resistance

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    Kristensen, Jonas Møller; Skov, Vibe; Petersson, Stine Juhl

    2014-01-01

    Insulin resistance in obesity and type 2 diabetes is related to abnormalities in mitochondrial oxidative phosphorylation (OxPhos) in skeletal muscle. We tested the hypothesis that mitochondrial oxidative metabolism is impaired in muscle of patients with inherited insulin resistance and defective...... insulin signalling....

  10. A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells.

    Science.gov (United States)

    Shaham, Oded; Slate, Nancy G; Goldberger, Olga; Xu, Qiuwei; Ramanathan, Arvind; Souza, Amanda L; Clish, Clary B; Sims, Katherine B; Mootha, Vamsi K

    2010-01-26

    Mutations in either the mitochondrial or nuclear genomes can give rise to respiratory chain disease (RCD), a large class of devastating metabolic disorders. Their clinical management is challenging, in part because we lack facile and accurate biomarkers to aid in diagnosis and in the monitoring of disease progression. Here we introduce a sequential strategy that combines biochemical analysis of spent media from cell culture with analysis of patient plasma to identify disease biomarkers. First, we applied global metabolic profiling to spotlight 32 metabolites whose uptake or secretion kinetics were altered by chemical inhibition of the respiratory chain in cultured muscle . These metabolites span a wide range of pathways and include lactate and alanine, which are used clinically as biomarkers of RCD. We next measured the cell culture-defined metabolites in human plasma to discover that creatine is reproducibly elevated in two independent cohorts of RCD patients, exceeding lactate and alanine in magnitude of elevation and statistical significance. In cell culture extracellular creatine was inversely related to the intracellular phosphocreatine:creatine ratio suggesting that the elevation of plasma creatine in RCD patients signals a low energetic state of tissues using the phosphocreatine shuttle. Our study identifies plasma creatine as a potential biomarker of human mitochondrial dysfunction that could be clinically useful. More generally, we illustrate how spent media from cellular models of disease may provide a window into the biochemical derangements in human plasma, an approach that could, in principle, be extended to a range of complex diseases.

  11. Metabolic alkalosis reduces exercise-induced acidosis and potassium accumulation in human skeletal muscle interstitium

    DEFF Research Database (Denmark)

    Street, D.; Nielsen, Jens Jung; Bangsbo, Jens

    2005-01-01

    Skeletal muscle releases potassium during activity. Interstitial potassium accumulation is important for muscle function and the development of fatigue resulting from exercise. In the present study we used sodium citrate ingestion as a tool to investigate the relationship between interstitial H+ ...

  12. Muscle protein degradation and amino acid metabolism during prolonged knee-extensor exercise in humans

    DEFF Research Database (Denmark)

    Van Hall, Gerrit; Saltin, B; Wagenmakers, A J

    1999-01-01

    to a substantial increase in net muscle protein degradation, and that a lowering of the starting muscle glycogen content leads to a further increase. The carbon atoms of the branched-chain amino acids (BCAA), glutamate, aspartate and asparagine, liberated by protein degradation, and the BCAA and glutamate...

  13. Metabolic costs of force generation for constant-frequency and catchlike-inducing electrical stimulation in human tibialis anterior muscle

    DEFF Research Database (Denmark)

    Ratkevicius, Aivaras; Quistorff, Bjørn

    2002-01-01

    generation. Our findings also suggest that catchlike-inducing stimulation produces larger forces in fatigued muscle than constant-frequency trains and thus may be beneficial for muscle training or rehabilitation when muscle loading needs to be maintained in repetitive contractions......./minus 1.0 micromol ATP/kg wet weight/Ncenter dots, respectively, P = 0.601). This suggests that the positive effects of catchlike-inducing stimulation on force maintenance are mediated by potentiated Ca(2+) release from the sarcoplasmic reticulum rather than by lower metabolic costs of muscle force......Metabolic costs of force generation were compared for constant-frequency and catchlike-inducing electrical stimulation. Repetitive catchlike-inducing trains consisted of 2 interpulse intervals (IPIs) at 12.5 ms, 1 IPI at 25 ms, and 5 IPIs at 50 ms. Constant-frequency trains consisted of 8 IPIs...

  14. Training and muscle ammonia and amino acid metabolism in humans during prolonged exercise

    DEFF Research Database (Denmark)

    Graham, T E; Turcotte, L P; Kiens, Bente

    1995-01-01

    We studied the responses of NH3 and amino acids (AA) to prolonged exercise (3 h) in trained (Tr; n = 6) and untrained (Utr; n = 6) men. Each subject exercised the knee extensor muscles of one leg at 60% of maximum capacity. Thigh blood flow and femoral arteriovenous differences (0, 30, 60, 120, 1...

  15. Reduced muscle activation during exercise related to brain oxygenation and metabolism in humans

    DEFF Research Database (Denmark)

    Rasmussen, Peter; Nielsen, Jannie; Overgaard, M

    2010-01-01

    Maximal exercise may be limited by central fatigue defined as an inability of the central nervous system to fully recruit the involved muscles. This study evaluated whether a reduction in the cerebral oxygen-to-carbohydrate index (OCI) and in the cerebral mitochondrial oxygen tension relate...

  16. Aerobic metabolism of human quadriceps muscle: in vivo data parallel measurements on isolated mitochondria

    DEFF Research Database (Denmark)

    Rasmussen, Ulla Fugmann; Rasmussen, Hans N.; Krustrup, Peter

    2001-01-01

    -18 mmol O2 · min 1 · kg 1 at work rates of 22-32 W/kg). Mitochondria were isolated from the same muscle at rest. Strong correlations were obtained between O2 max and a number of mitochondrial parameters (mitochondrial protein, cytochrome aa3, citrate synthase, and respiratory activities). The activities...

  17. Glucagon Like Peptide-1-Induced Glucose Metabolism in Differentiated Human Muscle Satellite Cells Is Attenuated by Hyperglycemia

    Science.gov (United States)

    Green, Charlotte J.; Henriksen, Tora I.; Pedersen, Bente K.; Solomon, Thomas P. J.

    2012-01-01

    Background Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined. Methods Skeletal muscle satellite cells isolated from young (22.5±0.97 yr), lean (BMI 22.5±0.6 kg/m2), healthy males were differentiated in media containing either 22.5 mM (high) or 5 mM (normal) glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis. Results We firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes). Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose) conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia. Conclusions GLP-1 increases glucose uptake and glycogen synthesis into fully-differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation of both GLP-1 and

  18. Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia.

    Directory of Open Access Journals (Sweden)

    Charlotte J Green

    Full Text Available BACKGROUND: Glucagon like peptide-1 (GLP-1 stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined. METHODS: Skeletal muscle satellite cells isolated from young (22.5 ± 0.97 yr, lean (BMI 22.5 ± 0.6 kg/m(2, healthy males were differentiated in media containing either 22.5 mM (high or 5 mM (normal glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis. RESULTS: We firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes. Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia. CONCLUSIONS: GLP-1 increases glucose uptake and glycogen synthesis into fully-differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation

  19. Metabolic, enzymatic, and transporter responses in human muscle during three consecutive days of exercise and recovery.

    Science.gov (United States)

    Green, Howard J; Bombardier, Eric; Duhamel, Todd A; Stewart, Riley D; Tupling, A Ross; Ouyang, Jing

    2008-10-01

    This study investigated the responses in substrate- and energy-based properties to repetitive days of prolonged submaximal exercise and recovery. Twelve untrained volunteers (Vo(2)(peak) = 44.8 +/- 2.0 ml.kg(-1).min(-1), mean +/- SE) cycled ( approximately 60 Vo(2)(peak)) on three consecutive days followed by 3 days of recovery. Tissue samples were extracted from the vastus lateralis both pre- and postexercise on day 1 (E1), day 3 (E3), and during recovery (R1, R2, R3) and were analyzed for changes in metabolism, substrate, and enzymatic and transporter responses. For the metabolic properties (mmol/kg(-1) dry wt), exercise on E1 resulted in reductions (P transporters, the experimental protocol resulted in a decrease (P glucose transporter-1 (GLUT1; 29% by R1), an increase in GLUT4 (29% by E3), and increases (P transporters (MCT) (for MCT1, 23% by R2 and for MCT4, 18% by R1). Of the mitochondrial and cytosolic enzyme activities examined, cytochrome c oxidase (COX), and hexokinase were both reduced (P glucose and lactate transporters are among the earliest adaptive responses of substrate and metabolic properties studied to the sudden onset of regular low-intensity exercise.

  20. Human skeletal muscle energy metabolism: when a physiological model promotes the search for new technologies.

    Science.gov (United States)

    Binzoni, Tiziano

    2003-10-01

    The idea that muscle function and, in fact, the function of all living tissues may be described by physical laws appeared in the second half of the 19th century. During this period, Helmoltz (Uber die Erhaltung der Kraft, 1847) showed that the principle of energy conservation may be applied to living systems. In the field of exercise physiology, this idea has been subsequently developed by Rodolfo Margaria's (1901-1983) School and the mathematical formalization of the theory has succeeded in the bioenergetic model. During the last 20 years methodical and critical study of the bioenergetic model has been carried out by Paolo Cerretelli, one of the most important heirs of Rodolfo Margaria's School. Original results and technological developments have been generated by his activity and many young scientists have been educated in this approach. The present paper wants to present the modern history of the bioenergetic model and is dedicated to Paolo Cerretelli on the occasion of his seventieth birthday.

  1. Genetically Determined Insulin Resistance is Characterized by Down-Regulation of Mitochondrial Oxidative Metabolism in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Kristensen, Jonas M; Skov, Vibe; Wojtaszewski, Jørgen

    2010-01-01

    mitochondrial dysfunction is a cause or consequence of insulin resistance remains to be clarified. In the present study, we tested the hypothesis that mitochondrial oxidative metabolism was down-regulated in skeletal muscle of patients with genetically determined insulin resistance. Skeletal muscle biopsies......Transcriptional profiling of skeletal muscle from patients with type 2 diabetes and high-risk individuals have demonstrated a co-ordinated down-regulation of oxidative phosphorylation (OxPhos) genes, suggesting a link between insulin resistance and mitochondrial dysfunction. However, whether...... obtained during a euglycemic-hyperinsulinemic clamp in heterozygote carriers (n=6) of a mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene (INSR) and matched healthy controls (n=11) were used for transcriptional profiling. Biological pathways analysis was performed using Gene...

  2. Exercise, sex, menstrual cycle phase, and 17beta-estradiol influence metabolism-related genes in human skeletal muscle.

    Science.gov (United States)

    Fu, Ming-hua H; Maher, Amy C; Hamadeh, Mazen J; Ye, Changhua; Tarnopolsky, Mark A

    2009-12-30

    Higher fat and lower carbohydrate and amino acid oxidation are observed in women compared with men during endurance exercise. We hypothesized that the observed sex difference is due to estrogen and that menstrual cycle phase or supplementation of men with 17beta-estradiol (E(2)) would coordinately influence the mRNA content of genes involved in lipid and/or carbohydrate metabolism in skeletal muscle. Twelve men and twelve women had muscle biopsies taken before and immediately after 90 min of cycling at 65% peak oxygen consumption (Vo(2peak)). Women were studied in the midfollicular (Fol) and midluteal (Lut) phases, and men were studied after 8 days of E(2) or placebo supplementation. Targeted RT-PCR was used to compare mRNA content for genes involved in transcriptional regulation and lipid, carbohydrate, and amino acid metabolism. Sex was the greatest predictor of substrate metabolism gene content. Sex affected the mRNA content of FATm, FABPc, SREBP-1c, mtGPAT, PPARdelta, PPARalpha, CPTI, TFP-alpha, GLUT4, HKII, PFK, and BCOADK (P Menstrual cycle had a small effect on PPARdelta, GP, and glycogenin mRNA content. Overall, women have greater mRNA content for several genes involved in lipid metabolism, which is partially due to an effect of E(2).

  3. The metabolomic profile of gamma-irradiated human hepatoma and muscle cells reveals metabolic changes consistent with the Warburg effect

    Directory of Open Access Journals (Sweden)

    Min Wang

    2016-01-01

    Full Text Available The two human cell lines HepG2 from hepatoma and HMCL-7304 from striated muscle were γ-irradiated with doses between 0 and 4 Gy. Abundant γH2AX foci were observed at 4 Gy after 4 h of culture post-irradiation. Sham-irradiated cells showed no γH2AX foci and therefore no signs of radiation-induced double-strand DNA breaks. Flow cytometry indicated that 41.5% of HepG2 cells were in G2/M and this rose statistically significantly with increasing radiation dose reaching a plateau at ∼47%. Cell lysates from both cell lines were subjected to metabolomic analysis using Gas Chromatography-Mass Spectrometry (GCMS. A total of 46 metabolites could be identified by GCMS in HepG2 cell lysates and 29 in HMCL-7304 lysates, most of which occurred in HepG2 cells. Principal Components Analysis (PCA showed a clear separation of sham, 1, 2 and 4 Gy doses. Orthogonal Projection to Latent Structures-Discriminant Analysis (OPLS-DA revealed elevations in intracellular lactate, alanine, glucose, glucose 6-phosphate, fructose and 5-oxoproline, which were found by univariate statistics to be highly statistically significantly elevated at both 2 and 4 Gy compared with sham irradiated cells. These findings suggested upregulation of cytosolic aerobic glycolysis (the Warburg effect, with potential shunting of glucose through aldose reductase in the polyol pathway, and consumption of reduced Glutathione (GSH due to γ-irradiation. In HMCL-7304 myotubes, a putative Warburg effect was also observed only at 2 Gy, albeit a lesser magnitude than in HepG2 cells. It is anticipated that these novel metabolic perturbations following γ-irradiation of cultured cells will lead to a fuller understanding of the mechanisms of tissue damage following ionizing radiation exposure.

  4. Studies of gene expression and activity of hexokinase, phosphofructokinase and glycogen synthase in human skeletal muscle in states of altered insulin-stimulated glucose metabolism

    DEFF Research Database (Denmark)

    Vestergaard, H

    1999-01-01

    of the review is to discuss our present knowledge of the activities and gene expression of hexokinase II (HKII), phosphofructokinase (PFK) and glycogen synthase (GS) in human skeletal muscle in states of altered insulin-stimulated glucose metabolism. My own experimental studies have comprised patients...... proximal to the GS protein. In insulin resistant diabetic patients the impact of these yet unknown abnormalities may be accentuated by the prevailing hyperglycaemia and hyperlipidaemia. Endurance training in young healthy subjects results in improved insulin-stimulated glucose disposal rates, predominantly......-stimulated glucose oxidation rate at the whole body level and PFK activity in muscle are normal. In parallel, no changes have been found in skeletal muscle levels of PFK mRNA and immunoreactive protein in NIDDM or IDDM patients. In endurance trained subjects insulin-stimulated whole body glucose oxidation rate...

  5. Cytokines: muscle protein and amino acid metabolism

    DEFF Research Database (Denmark)

    van Hall, Gerrit

    2012-01-01

    raises TNF-α and IL-6 to moderate levels, has only identified IL-6 as a potent cytokine, decreasing systemic amino acid levels and muscle protein metabolism. The marked decrease in circulatory and muscle amino acid concentrations was observed with a concomitant reduction in both the rates of muscle...... of IL-6 on the regulation of muscle protein metabolism but indirectly via IL-6 reducing amino acid availability. SUMMARY: Recent studies suggest that the best described cytokines TNF-α and IL-6 are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However...

  6. Acute low-intensity cycling with blood-flow restriction has no effect on metabolic signaling in human skeletal muscle compared to traditional exercise.

    Science.gov (United States)

    Smiles, William J; Conceição, Miguel S; Telles, Guilherme D; Chacon-Mikahil, Mara P T; Cavaglieri, Cláudia R; Vechin, Felipe C; Libardi, Cleiton A; Hawley, John A; Camera, Donny M

    2017-02-01

    Autophagy is an intracellular degradative system sensitive to hypoxia and exercise-induced perturbations to cellular bioenergetics. We determined the effects of low-intensity endurance-based exercise performed with blood-flow restriction (BFR) on cell signaling adaptive responses regulating autophagy and substrate metabolism in human skeletal muscle. In a randomized cross-over design, nine young, healthy but physically inactive males completed three experimental trials separated by 1 week of recovery consisting of either a resistance exercise bout (REX: 4 × 10 leg press repetitions, 70% 1-RM), endurance exercise (END: 30 min cycling, 70% VO2peak), or low-intensity cycling with BFR (15 min, 40% VO2peak). A resting muscle biopsy was obtained from the vastus lateralis 2 weeks prior to the first exercise trial and 3 h after each exercise bout. END increased ULK1Ser757 phosphorylation above rest and BFR (~37 to 51%, P exercise-induced changes in select markers of autophagy following BFR. Genes implicated in substrate metabolism (HK2 and PDK4) were increased above rest (~143 to 338%) and BFR cycling (~212 to 517%) with END (P < 0.001). A single bout of low-intensity cycling with BFR is insufficient to induce intracellular "stress" responses (e.g., high rates of substrate turnover and local hypoxia) necessary to activate skeletal muscle autophagy signaling.

  7. Substrate kinetics in patients with disorders of skeletal muscle metabolism.

    Science.gov (United States)

    Ørngreen, Mette Cathrine

    2016-07-01

    The main purpose of the following studies was to investigate pathophysiological mechanisms in fat and carbohydrate metabolism and effect of nutritional interventions in patients with metabolic myopathies and in patients with severe muscle wasting. Yet there is no cure for patients with skeletal muscle disorders. The group of patients is heterozygous and this thesis is focused on patients with metabolic myopathies and low muscle mass due to severe muscle wasting. Disorders of fatty acid oxidation (FAO) are, along with myophosphorylase deficiency (McArdle disease), the most common inborn errors of metabolism leading to recurrent episodes of rhabdomyolysis in adults. Prolonged exercise, fasting, and fever are the main triggering factors for rhabdomyolysis in these conditions, and can be complicated by acute renal failure. Patients with low muscle mass are in risk of loosing their functional skills and depend on a wheel chair and respiratory support. We used nutritional interventions and metabolic studies with stable isotope technique and indirect calorimetry in patients with metabolic myopathies and patients with low muscle mass to get information of the metabolism of the investigated diseases, and to gain knowledge of the biochemical pathways of intermediary metabolism in human skeletal muscle. We have shown that patients with fat metabolism disorders in skeletal muscle affecting the transporting enzyme of fat into the mitochondria (carnitine palmitoyltransferase II deficiency) and affecting the enzyme responsible for breakdown of the long-chain fatty acids (very long chain acyl-CoA dehydrogenase deficiency) have a normal fatty acid oxidation at rest, but enzyme activity is too low to increase fatty acid oxidation during exercise. Furthermore, these patients benefit from a carbohydrate rich diet. Oppositely is exercise capacity worsened by a fat-rich diet in these patients. The patients also benefit from IV glucose, however, when glucose is given orally just before

  8. Interactions between muscle tissues and bone metabolism.

    Science.gov (United States)

    Kawao, Naoyuki; Kaji, Hiroshi

    2015-05-01

    Sarcopenia and osteoporosis have recently been noted for their relationship with locomotive syndrome and increased number of older people. Sarcopenia is defined by decreased muscle mass and impaired muscle function, which may be associated with frailty. Several clinical data have indicated that increased muscle mass is related to increased bone mass and reduced fracture risk. Genetic, endocrine and mechanical factors as well as inflammatory and nutritional states concurrently affect muscle tissues and bone metabolism. Several genes, including myostatin and α-actinin 3, have been shown in a genome-wide association study (GWAS) to be associated with both sarcopenia and osteoporosis. Vitamin D, growth hormone and testosterone as well as pathological disorders, such as an excess in glucocorticoid and diabetes, affect both muscle and bone. Basic and clinical research of bone metabolism and muscle biology suggests that bone interacts with skeletal muscle via signaling from local and humoral factors in addition to their musculoskeletal function. However, the physiological and pathological mechanisms related to muscle and bone interactions remain unclear. We found that Tmem119 may play a critical role in the commitment of myoprogenitor cells to the osteoblast lineage. We also reported that osteoglycin and FAM5C might be muscle-derived humoral osteogenic factors. Other factors, including myostatin, osteonectin, insulin-like growth factor I, irisin and osteocalcin, may be associated with the interactions between muscle tissues and bone metabolism. © 2014 Wiley Periodicals, Inc.

  9. Glycogen metabolism in humans ? ??

    OpenAIRE

    Adeva-Andany, María M.; González-Lucán, Manuel; Donapetry-García, Cristóbal; Fernández-Fernández, Carlos; Ameneiros-Rodríguez, Eva

    2016-01-01

    In the human body, glycogen is a branched polymer of glucose stored mainly in the liver and the skeletal muscle that supplies glucose to the blood stream during fasting periods and to the muscle cells during muscle contraction. Glycogen has been identified in other tissues such as brain, heart, kidney, adipose tissue, and erythrocytes, but glycogen function in these tissues is mostly unknown. Glycogen synthesis requires a series of reactions that include glucose entrance into the cell through...

  10. Regulation of PGC-1α and exercise training-induced metabolic adaptations in skeletal muscle

    DEFF Research Database (Denmark)

    Brandt, Nina

    -induced improvements in skeletal muscle metabolic capacity, but may contribute to the exercise training-induced maintenance of skeletal muscle mass. In addition, the results indicate an exercise intensity dependent regulation of autophagy in skeletal muscle and suggest that PGC-1 α regulates both acute and exercise...... and intracellular signalling in human skeletal muscle depend on adrenaline levels or metabolic stress. 2) PGC-1α mediated exercise and exercise training-induced adaptive metabolic responses in mouse skeletal muscle depend on exercise intensity. 3) β-adrenergic signalling contributes to exercise training......-induced metabolic adaptations in mouse skeletal muscle through PGC-1α . Paper I demonstrated that di erences in plasma adrenaline and muscle metabolic stress during exercise do not reinforce exercise-induced PGC-1 α mRNA response in human skeletal muscle. In addition, di erences in exercise-induced AMPK and p38...

  11. An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

    Science.gov (United States)

    Vailas, Arthur C.; Martinez, Daniel A.

    1999-01-01

    Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, media] gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

  12. Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin

    DEFF Research Database (Denmark)

    Robach, Paul; Recalcati, Stefania; Girelli, Domenico

    2009-01-01

    no appreciable change in myoglobin levels was observed, which suggests unaltered muscle oxygen homeostasis. In conclusion, under rhEpo stimulation, the changes in the expression of muscle iron proteins indicate the occurrence of skeletal muscle iron accumulation despite the remarkable hepcidin suppression...

  13. AMPK in skeletal muscle function and metabolism

    DEFF Research Database (Denmark)

    Kjøbsted, Rasmus; Hingst, Janne R; Fentz, Joachim

    2017-01-01

    Skeletal muscle possesses a remarkable ability to adapt to various physiologic conditions. AMPK is a sensor of intracellular energy status that maintains energy stores by fine-tuning anabolic and catabolic pathways. AMPK's role as an energy sensor is particularly critical in tissues displaying...... highly changeable energy turnover. Due to the drastic changes in energy demand that occur between the resting and exercising state, skeletal muscle is one such tissue. Here, we review the complex regulation of AMPK in skeletal muscle and its consequences on metabolism (e.g., substrate uptake, oxidation......, and storage as well as mitochondrial function of skeletal muscle fibers). We focus on the role of AMPK in skeletal muscle during exercise and in exercise recovery. We also address adaptations to exercise training, including skeletal muscle plasticity, highlighting novel concepts and future perspectives...

  14. Muscle glucose metabolism in chronic obstructive pulmonary disease patients.

    Science.gov (United States)

    Sancho-Muñoz, Antonio; Trampal, Carlos; Pascual, Sergi; Martínez-Llorens, Juana; Chalela, Roberto; Gea, Joaquim; Orozco-Levi, Mauricio

    2014-06-01

    Muscle dysfunction is one of the most extensively studied manifestations of COPD. Metabolic changes in muscle are difficult to study in vivo, due to the lack of non-invasive techniques. Our aim was to evaluate metabolic activity simultaneously in various muscle groups in COPD patients. Thirty-nine COPD patients and 21 controls with normal lung function, due to undergo computed axial and positron emission tomography for staging of localized lung lesions were included. After administration of 18-fluordeoxyglucose, images of 2 respiratory muscles (costal and crural diaphragm, and rectus abdominus) and 2 peripheral muscles (brachial biceps and quadriceps) were obtained, using the standard uptake value as the glucose metabolism index. Standard uptake value was higher in both portions of the diaphragm than in the other muscles of all subjects. Moreover, the crural diaphragm and rectus abdominus showed greater activity in COPD patients than in the controls (1.8±0.7 vs 1.4±0.8; and 0.78±0.2 vs 0.58±0.1; respectively, P<.05). A similar trend was observed with the quadriceps. In COPD patients, uptake in the two respiratory muscles and the quadriceps correlated directly with air trapping (r=0.388, 0.427 and 0.361, respectively, P<.05). There is greater glucose uptake and metabolism in the human diaphragm compared to other muscles when the subject is at rest. Increased glucose metabolism in the respiratory muscles (with a similar trend in their quadriceps) of COPD patients is confirmed quantitatively, and is directly related to the mechanical loads confronted. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

  15. Muscle perfusion and metabolic heterogeneity: insights from noninvasive imaging techniques

    DEFF Research Database (Denmark)

    Kalliokoski, Kari K; Scheede-Bergdahl, Celena; Kjaer, Michael

    2006-01-01

    Recent developments in noninvasive imaging techniques have enabled the study of local changes in perfusion and metabolism in skeletal muscle as well as patterns of heterogeneity in these variables in humans. In this review, the principles of these techniques along with some recent findings...

  16. Role of PKCδ in Insulin Sensitivity and Skeletal Muscle Metabolism

    DEFF Research Database (Denmark)

    Li, Mengyao; Vienberg, Sara G; Bezy, Olivier

    2015-01-01

    metabolism by generating mice in which PKCδ was deleted specifically in muscle using Cre-lox recombination. Deletion of PKCδ in muscle improved insulin signaling in young mice, especially at low insulin doses; however, this did not change glucose tolerance or insulin tolerance tests done with pharmacological......-body insulin sensitivity and muscle insulin resistance and by 15 months of age improved the age-related decline in whole-body glucose tolerance. At 15 months of age, M-PKCδKO mice also exhibited decreased metabolic rate and lower levels of some proteins of the OXPHOS complex suggesting a role for PKCδ......Protein kinase C (PKC)δ has been shown to be increased in liver in obesity and plays an important role in the development of hepatic insulin resistance in both mice and humans. In the current study, we explored the role of PKCδ in skeletal muscle in the control of insulin sensitivity and glucose...

  17. Skeletal muscle substrate metabolism during exercise: methodological considerations

    DEFF Research Database (Denmark)

    Van Hall, Gerrit; González-Alonso, J; Sacchetti, M

    1999-01-01

    The aim of the present article is to evaluate critically the various methods employed in studies designed to quantify precisely skeletal muscle substrate utilization during exercise. In general, the pattern of substrate utilization during exercise can be described well from O2 uptake measurements...... substrates. There are several methodological concerns to be aware of when studying the metabolic response to exercise in human subjects. These concerns include: (1) the muscle mass involved in the exercise is largely unknown (bicycle or treadmill). Moreover, whether the muscle sample obtained from a limb...

  18. Glycogen synthesis in human gastrocnemius muscle is not representative of whole-body muscle glycogen synthesis

    NARCIS (Netherlands)

    Serlie, Mireille J. M.; de Haan, Jacco H.; Tack, Cees J.; Verberne, Hein J.; Ackermans, Mariette T.; Heerschap, Arend; Sauerwein, Hans P.

    2005-01-01

    The introduction of C-13 magnetic resonance spectroscopy (MRS) has enabled noninvasive measurement of muscle glycogen synthesis in humans. Conclusions based on measurements by the MRS technique assume that glucose metabolism in gastrocnemius muscle is representative for all skeletal muscles and thus

  19. Glycogen synthesis in human gastrocnemius muscle is not representative of whole-body muscle glycogen synthesis.

    NARCIS (Netherlands)

    Serlie, M.J.; Haan, J.H.A. de; Tack, C.J.J.; Verberne, H.J.; Ackermans, M.T.; Heerschap, A.; Sauerwein, H.P.

    2005-01-01

    The introduction of 13C magnetic resonance spectroscopy (MRS) has enabled noninvasive measurement of muscle glycogen synthesis in humans. Conclusions based on measurements by the MRS technique assume that glucose metabolism in gastrocnemius muscle is representative for all skeletal muscles and thus

  20. Impact of adrenaline and metabolic stress on exercise-induced intracellular signaling and PGC-1α mRNA response in human skeletal muscle

    DEFF Research Database (Denmark)

    Brandt, Nina; Gunnarsson, Thomas Gunnar Petursson; Hostrup, Morten

    2016-01-01

    This study tested the hypothesis that elevated plasma adrenaline or metabolic stress enhances exercise-induced PGC-1α mRNA and intracellular signaling in human muscle. Trained (VO2-max: 53.8 ± 1.8 mL min(-1) kg(-1)) male subjects completed four different exercise protocols (work load of the legs...... was matched): C - cycling at 171 ± 6 W for 60 min (control); A - cycling at 171 ± 6 W for 60 min, with addition of intermittent arm exercise (98 ± 4 W). DS - cycling at 171 ± 6 W interspersed by 30 sec sprints (513 ± 19 W) every 10 min (distributed sprints); and CS - cycling at 171 ± 6 W for 40 min followed...

  1. Single Muscle Fiber Proteomics Reveals Fiber-Type-Specific Features of Human Muscle Aging

    Directory of Open Access Journals (Sweden)

    Marta Murgia

    2017-06-01

    Full Text Available Skeletal muscle is a key tissue in human aging, which affects different muscle fiber types unequally. We developed a highly sensitive single muscle fiber proteomics workflow to study human aging and show that the senescence of slow and fast muscle fibers is characterized by diverging metabolic and protein quality control adaptations. Whereas mitochondrial content declines with aging in both fiber types, glycolysis and glycogen metabolism are upregulated in slow but downregulated in fast muscle fibers. Aging mitochondria decrease expression of the redox enzyme monoamine oxidase A. Slow fibers upregulate a subset of actin and myosin chaperones, whereas an opposite change happens in fast fibers. These changes in metabolism and sarcomere quality control may be related to the ability of slow, but not fast, muscle fibers to maintain their mass during aging. We conclude that single muscle fiber analysis by proteomics can elucidate pathophysiology in a sub-type-specific manner.

  2. Pro-inflammatory macrophages increase in skeletal muscle of high fat-fed mice and correlate with metabolic risk markers in humans.

    Science.gov (United States)

    Fink, Lisbeth N; Costford, Sheila R; Lee, Yun S; Jensen, Thomas E; Bilan, Philip J; Oberbach, Andreas; Blüher, Matthias; Olefsky, Jerrold M; Sams, Anette; Klip, Amira

    2014-03-01

    In obesity, immune cells infiltrate adipose tissue. Skeletal muscle is the major tissue of insulin-dependent glucose disposal, and indices of muscle inflammation arise during obesity, but whether and which immune cells increase in muscle remain unclear. Immune cell presence in quadriceps muscle of wild type mice fed high-fat diet (HFD) was studied for 3 days to 10 weeks, in CCL2-KO mice fed HFD for 1 week, and in human muscle. Leukocyte presence was assessed by gene expression of lineage markers, cyto/chemokines and receptors; immunohistochemistry; and flow cytometry. After 1 week HFD, concomitantly with glucose intolerance, muscle gene expression of Ly6b, Emr1 (F4/80), Tnf, Ccl2, and Ccr2 rose, as did pro- and anti-inflammatory markers Itgax (CD11c) and Mgl2. CD11c+ proinflammatory macrophages in muscle increased by 76%. After 10 weeks HFD, macrophages in muscle increased by 47%. Quadriceps from CCL2-KO mice on HFD did not gain macrophages and maintained insulin sensitivity. Muscle of obese, glucose-intolerant humans showed elevated CD68 (macrophage marker) and ITGAX, correlating with poor glucose disposal and adiposity. Mouse and human skeletal muscles gain a distinct population of inflammatory macrophages upon HFD or obesity, linked to insulin resistance in humans and CCL2 availability in mice. © 2013 The Obesity Society.

  3. Lactate oxidation in human skeletal muscle mitochondria

    DEFF Research Database (Denmark)

    Jacobs, Robert A; Meinild, Anne-Kristine; Nordsborg, Nikolai B

    2013-01-01

    Lactate is an important intermediate metabolite in human bioenergetics and is oxidized in many different tissues including the heart, brain, kidney, adipose tissue, liver, and skeletal muscle. The mechanism(s) explaining the metabolism of lactate in these tissues, however, remains unclear. Here, we...... analyze the ability of skeletal muscle to respire lactate by using an in situ mitochondrial preparation that leaves the native tubular reticulum and subcellular interactions of the organelle unaltered. Skeletal muscle biopsies were obtained from vastus lateralis muscle in 16 human subjects. Samples were...... of four separate and specific substrate titration protocols, the respirometric analysis revealed that mitochondria were capable of oxidizing lactate in the absence of exogenous LDH. The titration of lactate and NAD(+) into the respiration medium stimulated respiration (P = 0.003). The addition...

  4. Human Body Exergy Metabolism

    OpenAIRE

    Mady, Carlos

    2013-01-01

    The exergy analysis of the human body is a tool that can provide indicators of health and life quality. To perform the exergy balance it is necessary to calculate the metabolism on an exergy basis, or metabolic exergy, although there is not yet consensus in its calculation procedure. Hence, the aim of this work is to provide a general method to evaluate this physical quantity for human body based on indirect calorimetry data. To calculate the metabolism on an exergy basis it is necessary to d...

  5. Responses of algesic and metabolic substances to 8h of repetitive manual work in myalgic human trapezius muscle

    DEFF Research Database (Denmark)

    Larsson, B; Rosendal, L; Kristiansen, J

    2008-01-01

    The trapezius muscle often develops pain as the result of repetitive and stressful work tasks although it is unclear to what extent this pain is due to alterations in muscle concentrations of algesic/nociceptive substances. Twenty women with chronic neck- and shoulder pain (TM) whose work required...... highly repetitive work tasks and 20 pain-free female colleagues (CON) were studied during and after a full 8-hour workday. We collected microdialysates from their dominant/most painful trapezius muscle; concentrations of serotonin, glutamate, lactate, pyruvate, potassium, bradykinin, and cytokines...... and blood flow were determined. In addition, we measured surface electromyogram, task exposure level, pain intensity, perceived mental stress, and urine-cortisol. In connection to the clinical neck and shoulder examination, we determined pressure pain thresholds (PPTs) over the trapezius and tibialis...

  6. Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia

    DEFF Research Database (Denmark)

    Green, Charlotte J; Henriksen, Tora I; Pedersen, Bente K

    2012-01-01

    Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the...

  7. Responses of algesic and metabolic substances to 8h of repetitive manual work in myalgic human trapezius muscle

    DEFF Research Database (Denmark)

    Larsson, B.; Rosendal, L.; Kristiansen, J.

    2008-01-01

    highly repetitive work tasks and 20 pain-free female colleagues (CON) were studied during and after a full 8-hour workday. We collected microdialysates from their dominant/most painful trapezius muscle; concentrations of serotonin, glutamate, lactate, pyruvate, potassium, bradykinin, and cytokines...

  8. Skeletal muscle metabolic characteristics before and after energy restriction in human obesity: fibre type, enzymatic beta-oxidative capacity and fatty acid-binding protein content.

    NARCIS (Netherlands)

    Kempen, K.P.G.; Saris, W.H.M.; Kuipers, H.; Glatz, J.F.; van der Vusse, G.J.

    1998-01-01

    University of Maastricht, Maastricht, The Netherlands. BACKGROUND: Skeletal muscle has the ability to adapt as result of dietary, hormonal or pharmacological interventions affecting energy metabolism. The aim of the present study was to investigate the effects of energy restriction on skeletal

  9. Arachidonate metabolism in bovine gallbladder muscle

    Energy Technology Data Exchange (ETDEWEB)

    Nakano, M.; Hidaka, T.; Ueta, T.; Ogura, R.

    1983-04-01

    Incubation of (1-/sup 14/C)arachidonic acid (AA) with homogenates of bovine gallbladder muscle generated a large amount of radioactive material having the chromatographic mobility of 6-keto-PGF1 alpha (stable product of PGI2) and smaller amounts of products that comigrated with PGF2 alpha PGE2. Formation of these products was inhibited by the cyclooxygenase inhibitor indomethacin. The major radioactive product identified by thin-layer chromatographic mobility and by gas chromatography - mass spectrometric analysis was found to be 6-keto-PGF1 alpha. The quantitative metabolic pattern of (1-/sup 14/C)PGH2 was virtually identical to that of (1-/sup 14/C)AA. Incubation of arachidonic acid with slices of bovine gallbladder muscle released labile anti-aggregatory material in the medium, which was inhibited by aspirin or 15-hydroperoxy-AA. These results indicate that bovine gallbladder muscle has a considerable enzymatic capacity to produce PGI2 from arachidonic acid.

  10. Human airway smooth muscle

    NARCIS (Netherlands)

    J.C. de Jongste (Johan)

    1987-01-01

    textabstractThe function of airway smooth muscle in normal subjects is not evident. Possible physiological roles include maintenance of optimal regional ventilation/perfusion ratios, reduction of anatomic dead space, stabilisation of cartilaginous bronchi, defense against impurities and, less

  11. Human airway smooth muscle

    OpenAIRE

    Jongste, Johan

    1987-01-01

    textabstractThe function of airway smooth muscle in normal subjects is not evident. Possible physiological roles include maintenance of optimal regional ventilation/perfusion ratios, reduction of anatomic dead space, stabilisation of cartilaginous bronchi, defense against impurities and, less likely, squeezing mucus out of mucous glands and pulling open the alveoli next to the airways1 . Any role of airway smooth muscle is necessarily limited, because an important degree of contraction will l...

  12. Using exercise training to understand control of skeletal muscle metabolism.

    Science.gov (United States)

    Gibala, Martin J

    2017-01-01

    Bengt Saltin believed that exercise was the unsurpassed tool to study human integrative physiology. He demonstrated this over the course of his career by employing physical training as a model to advance our understanding of skeletal muscle metabolic control and the impact of physical activity on performance and health. Bengt was also a pioneer in advocating the concept of exercise is medicine. His scientific curiosity was perhaps exceeded only by his generosity.

  13. A systems biology approach reveals a link between systemic cytokines and skeletal muscle energy metabolism in a rodent smoking model and human COPD.

    Science.gov (United States)

    Davidsen, Peter K; Herbert, John M; Antczak, Philipp; Clarke, Kim; Ferrer, Elisabet; Peinado, Victor I; Gonzalez, Constancio; Roca, Josep; Egginton, Stuart; Barberá, Joan A; Falciani, Francesco

    2014-01-01

    A relatively large percentage of patients with chronic obstructive pulmonary disease (COPD) develop systemic co-morbidities that affect prognosis, among which muscle wasting is particularly debilitating. Despite significant research effort, the pathophysiology of this important extrapulmonary manifestation is still unclear. A key question that remains unanswered is to what extent systemic inflammatory mediators might play a role in this pathology. Cigarette smoke (CS) is the main risk factor for developing COPD and therefore animal models chronically exposed to CS have been proposed for mechanistic studies and biomarker discovery. Although mice have been successfully used as a pre-clinical in vivo model to study the pulmonary effects of acute and chronic CS exposure, data suggest that they may be inadequate models for studying the effects of CS on peripheral muscle function. In contrast, recent findings indicate that the guinea pig model (Cavia porcellus) may better mimic muscle wasting. We have used a systems biology approach to compare the transcriptional profile of hindlimb skeletal muscles from a Guinea pig rodent model exposed to CS and/or chronic hypoxia to COPD patients with muscle wasting. We show that guinea pigs exposed to long-term CS accurately reflect most of the transcriptional changes observed in dysfunctional limb muscle of severe COPD patients when compared to matched controls. Using network inference, we could then show that the expression profile in whole lung of genes encoding for soluble inflammatory mediators is informative of the molecular state of skeletal muscles in the guinea pig smoking model. Finally, we show that CXCL10 and CXCL9, two of the candidate systemic cytokines identified using this pre-clinical model, are indeed detected at significantly higher levels in serum of COPD patients, and that their serum protein level is inversely correlated with the expression of aerobic energy metabolism genes in skeletal muscle. We conclude that

  14. Osmoregulatory processes and skeletal muscle metabolism

    Science.gov (United States)

    Boschmann, Michael; Gottschalk, Simone; Adams, Frauke; Luft, Friedrich C.; Jordan, Jens

    Prolonged microgravity during space flight is associated with a decrease in blood and extracellular volume. These changes in water and electrolyte balance might activate catabolic processes which contribute finally to the loss of muscle and bone mass and strength. Recently, we found a prompt increase that energy expenditure by about 30% in both normal and overweight men and women after drinking 500 ml water. This effect is mediated by an increased sympathetic nervous system activity, obviously secondary to stimulation of osmosensitive afferent neurons in the liver, and skeletal muscle is possibly one effector organ. Therefore, we tested the hypothesis that this thermogenic response to water is accompanied by a stimulation of aerobic glucose metabolism in skeletal muscle. To this end, 16 young healthy volunteers (8 men) were studied. After an overnight fast (12h), a microdialysis probe was implanted into the right M. quadriceps femoris vastus lateralis and subsequently perfused with Ringer's solution (+50 mM ethanol). After 1h, volunteers were asked to drink 500 ml water (22° C) followed by continuing microdialysis for another 90 min. Dialysates (15 min fractions) were analyzed for [ethanol], [glucose], [lactate], [pyruvate], and [glycerol] in order to assess changes in muscle tissue perfusion (ethanol dilution technique), glycolysis and lipolysis. Blood samples were taken and heart rate (HR) and blood pressure (BP) were monitored. Neither HR and systolic and diastolic BP, nor plasma [glucose], [lactate], [insulin], and [C peptide] changed significantly after water drinking. Also, tissue perfusion and dialysate [glucose] did not change significantly. However, dialysate [lactate] increased by about 10 and 20% and dialysate [pyruvate] by about 100 and 200% in men and women, respectively. In contrast, dialysate [glycerol] decreased by about 30 and 20% in men and women, respectively. Therefore, drinking of 500 ml water stimulates aerobic glucose metabolism and inhibits

  15. Enhanced muscle glucose metabolism after exercise

    DEFF Research Database (Denmark)

    Richter, Erik; Garetto, L P; Goodman, M N

    1984-01-01

    Studies in the rat suggest that after voluntary exercise there are two phases of glycogen repletion in skeletal muscle (preceding study). In phase I glucose utilization and glycogen synthesis are enhanced both in the presence and absence of insulin, whereas in phase II only the increase in the pr......Studies in the rat suggest that after voluntary exercise there are two phases of glycogen repletion in skeletal muscle (preceding study). In phase I glucose utilization and glycogen synthesis are enhanced both in the presence and absence of insulin, whereas in phase II only the increase...... in the presence of insulin is found. To determine whether these alterations and in particular those mediated by insulin are due to local or systemic factors, one hindlimb of an anesthetized rat was electrically stimulated, and both hindlimbs were perfused immediately thereafter. Glucose and glycogen metabolism...... in the stimulated leg closely mimicked that observed previously after voluntary exercise on a treadmill. With no insulin added to the perfusate, glucose incorporation into glycogen was markedly enhanced in muscles that were glycogen depleted as were the uptake of 2-deoxyglucose and 3-O-methylglucose. Likewise...

  16. Assessment of (patho)physiologic alterations in equine muscle metabolism

    OpenAIRE

    Westermann, C.M.

    2008-01-01

    This thesis focussed on the diagnostic use of metabolic products and enzymes found in plasma, urine and muscle of the horse, the identification of which can reveal physiological or pathological changes in muscle metabolism. In this thesis analyses of carbohydrate-, lipid- and protein metabolites have been performed as well as analyses of the purine nucleotide cycle, the creatine metabolism and the oxidative phosphorylation. With these analyses we studied metabolic myopathies in the horse as w...

  17. Effects of adrenaline on whole-body glucose metabolism and insulin-mediated regulation of glycogen synthase and PKB phosphorylation in human skeletal muscle.

    Science.gov (United States)

    Jensen, Jørgen; Ruge, Toralph; Lai, Yu-Chiang; Svensson, Maria K; Eriksson, Jan W

    2011-02-01

    In the present study, we investigated the effect of adrenaline on insulin-mediated regulation of glucose and fat metabolism with focus on regulation of skeletal muscle PKB, GSK-3, and glycogen synthase (GS) phosphorylation. Ten healthy subjects (5 men and 5 women) received a 240-minute intravenous infusion of adrenaline (0.05 μg/[kg min]) or saline; after 120 minutes, a hyperinsulinemic-euglycemic clamp was added. Adrenaline infusion increased blood glucose concentration by approximately 50%, but the hyperinsulinemic clamp normalized blood glucose within 30 minutes. Glucose infusion rate during the last hour was approximately 60% lower during adrenaline infusion compared with saline (4.3 ± 0.5 vs 11.2 ± 0.6 mg/kg lean body mass per minute). Insulin increased PKB Ser⁴⁷³, PKB Thr³⁰⁸, and GSK-3β Ser⁹ phosphorylation in skeletal muscles; coinfusion of adrenaline did not influence insulin-stimulated PKB and GSK-3 phosphorylation. Adrenaline alone did not influence phosphorylation of PKB and GSK-3β. Insulin increased GS fractional activity and decreased GS Ser⁶⁴¹ and Ser⁶⁴⁵,⁶⁴⁹,⁶⁵³,⁶⁵⁷ phosphorylation. In the presence of adrenaline, insulin did neither activate GS nor dephosphorylate GS Ser⁶⁴¹. Surprisingly, GS Ser⁷ phosphorylation was not influenced by adrenaline. Adrenaline increased plasma lactate concentration; and muscle glycogen content was reduced in skeletal muscle the day after adrenaline infusion, supporting that insulin does not stimulate glycogen synthesis in skeletal muscles when adrenaline is present. In conclusion, adrenaline did not influence basal or insulin-stimulated PKB and GSK-3β phosphorylation in muscles, but completely blocked insulin-mediated GS activation and Ser⁶⁴¹ dephosphorylation. Still, insulin normalized adrenaline-mediated hyperglycemia. © 2011 Elsevier Inc. All rights reserved.

  18. Assessment of (patho)physiologic alterations in equine muscle metabolism

    NARCIS (Netherlands)

    Westermann, C.M.

    2008-01-01

    This thesis focussed on the diagnostic use of metabolic products and enzymes found in plasma, urine and muscle of the horse, the identification of which can reveal physiological or pathological changes in muscle metabolism. In this thesis analyses of carbohydrate-, lipid- and protein metabolites

  19. Coordination of metabolic plasticity in skeletal muscle.

    Science.gov (United States)

    Hood, David A; Irrcher, Isabella; Ljubicic, Vladimir; Joseph, Anna-Maria

    2006-06-01

    Skeletal muscle is a highly malleable tissue, capable of pronounced metabolic and morphological adaptations in response to contractile activity (i.e. exercise). Each bout of contractile activity results in a coordinated alteration in the expression of a variety of nuclear DNA and mitochondrial DNA (mtDNA) gene products, leading to phenotypic adaptations. This results in an increase in muscle mitochondrial volume and changes in organelle composition, referred to as mitochondrial biogenesis. The functional consequence of this biogenesis is an improved resistance to fatigue. Signals initiated by the exercise bout involve changes in intracellular Ca2+ as well as alterations in energy status (i.e. ATP/ADP ratio) and the consequent activation of downstream kinases such as AMP kinase and Ca2+-calmodulin-activated kinases. These kinases activate transcription factors that bind DNA to affect the transcription of genes, the most evident manifestation of which occurs during the post-exercise recovery period when energy metabolism is directed toward anabolism, rather than contractile activity. An important protein that is affected by exercise is the transcriptional coactivator PGC-1alpha, which cooperates with multiple transcription factors to induce the expression of nuclear genes encoding mitochondrial proteins. Once translated in the cytosol, these mitochondrially destined proteins are imported into the mitochondrial outer membrane, inner membrane or matrix space via specific import machinery transport components. Contractile activity affects the expression of the import machinery, as well as the kinetics of import, thus facilitating the entry of newly synthesized proteins into the expanding organelle. An important set of proteins that are imported are the mtDNA transcription factors, which influence the expression and replication of mtDNA. While mtDNA contributes only 13 proteins to the synthesis of the organelle, these proteins are vital for the proper assembly of multi

  20. Demonstration of a day-night rhythm in human skeletal muscle oxidative capacity

    Directory of Open Access Journals (Sweden)

    Dirk van Moorsel

    2016-08-01

    Conclusions: Our results suggest that the biological clock drives robust rhythms in human skeletal muscle oxidative metabolism. It is tempting to speculate that disruption of these rhythms contribute to the deterioration of metabolic health associated with circadian misalignment.

  1. Palmitic acid follows a different metabolic pathway than oleic acid in human skeletal muscle cells; lower lipolysis rate despite an increased level of adipose triglyceride lipase

    NARCIS (Netherlands)

    Bakke, S.S.; Moro, C.; Nikolic, N.; Hessvik, N.P.; Badin, P.M.; Lauvhaug, L.; Fredriksson, K.; Hesselink, M.K.; Boekschoten, M.V.; Kersten, A.H.; Thoresen, G.H.; Rustan, A.C.

    2012-01-01

    Development of insulin resistance is positively associated with dietary saturated fatty acids and negatively associated with monounsaturated fatty acids. To clarify aspects of this difference we have compared the metabolism of oleic (OA, monounsaturated) and palmitic acids (PA, saturated) in human

  2. Role of plasma membrane transporters in muscle metabolism.

    OpenAIRE

    Zorzano, A; Fandos, C; Palacín, M

    2000-01-01

    Muscle plays a major role in metabolism. Thus it is a major glucose-utilizing tissue in the absorptive state, and changes in muscle insulin-stimulated glucose uptake alter whole-body glucose disposal. In some conditions, muscle preferentially uses lipid substrates, such as fatty acids or ketone bodies. Furthermore, muscle is the main reservoir of amino acids and protein. The activity of many different plasma membrane transporters, such as glucose carriers and transporters of carnitine, creati...

  3. A metabolic link to skeletal muscle wasting and regeneration

    Directory of Open Access Journals (Sweden)

    René eKoopman

    2014-02-01

    Full Text Available Due to its essential role in movement, insulating the internal organs, generating heat to maintain core body temperature, and acting as a major energy storage depot, any impairment to skeletal muscle structure and function may lead to an increase in both morbidity and mortality. In the context of skeletal muscle, altered metabolism is directly associated with numerous pathologies and disorders, including diabetes, and obesity, while many skeletal muscle pathologies have secondary changes in metabolism, including cancer cachexia, sarcopenia and the muscular dystrophies. Furthermore, the importance of cellular metabolism in the regulation of skeletal muscle stem cells is beginning to receive significant attention. Thus, it is clear that skeletal muscle metabolism is intricately linked to the regulation of skeletal muscle mass and regeneration. The aim of this review is to discuss some of the recent findings linking a change in metabolism to changes in skeletal muscle mass, as well as describing some of the recent studies in developmental, cancer and stem-cell biology that have identified a role for cellular metabolism in the regulation of stem cell function, a process termed ‘metabolic reprogramming’.

  4. Zilpaterol hydrochloride affects cellular muscle metabolism and lipid components of ten different muscles in feedlot heifers

    Science.gov (United States)

    This study determined if zilpaterol hydrochloride (ZH) altered muscle metabolism and lipid components of ten muscles. Crossbred heifers were either supplemented with ZH (n = 9) or not (Control; n = 10). Muscle tissue was collected (adductor femoris, biceps femoris, gluteus medius, infraspinatus, lat...

  5. Regenerating human muscle fibres express GLUT3 protein

    DEFF Research Database (Denmark)

    Gaster, M; Beck-Nielsen, H; Schrøder, H D

    2002-01-01

    The presence of the GLUT3 glucose transporter protein in human muscle cells is a matter of debate. The present study was designed to establish whether GLUT3 is expressed in mature human skeletal muscle fibres and, if so, whether its expression changes under different conditions, such as metabolic...... stress (obesity, obese non-insulin-dependent diabetes mellitus), hypertrophy (training), de- and reinnervation (amyotrophic lateral sclerosis) or regeneration (polymyositis). We used an immunohistochemical approach to detect and localise GLUT3. GLUT3 immunoreactivity was not detectable in adult skeletal...... muscle fibres, nor did metabolic stress, training or de- and re-innervation induce GLUT3 expression, while a few GLUT3 expressing fibres were seen in some cases of polymyositis. In contrast, GLUT4 was expressed in all investigated muscle fibres. GLUT3 immunoreactivity was found in perineural...

  6. Muscle-specific expression of hypoxia-inducible factor in human skeletal muscle

    DEFF Research Database (Denmark)

    Mounier, Rémi; Pedersen, Bente Klarlund; Plomgaard, Peter

    2010-01-01

    fibres that possess unique patterns of protein and gene expression, producing different capillarization and energy metabolism systems. In this work, we analysed HIF-1alpha mRNA and protein expression related to the fibre-type composition in untrained human skeletal muscle by obtaining muscle biopsies......Skeletal muscle is well known to exhibit a high degree of plasticity depending on environmental changes, such as various oxygen concentrations. Studies of the oxygen-sensitive subunit alpha of hypoxia-inducible factor-1 (HIF-1) are difficult owing to the large variety of functionally diverse muscle......alpha mRNA and protein owing to their higher oxidative capacity. We have shown, in normoxic conditions, a higher HIF-1alpha protein expression in predominantly oxidative muscles than in predominantly glycolytic muscles. However, the HIF-1alpha mRNA expression pattern was not in agreement with the HIF-1...

  7. Early metabolic changes measured by 1H MRS in healthy and dystrophic muscle after injury.

    Science.gov (United States)

    Xu, Su; Pratt, Stephen J P; Spangenburg, Espen E; Lovering, Richard M

    2012-09-01

    Skeletal muscle injury is often assessed by clinical findings (history, pain, tenderness, strength loss), by imaging, or by invasive techniques. The purpose of this work was to determine if in vivo proton magnetic resonance spectroscopy ((1)H MRS) could reveal metabolic changes in murine skeletal muscle after contraction-induced injury. We compared findings in the tibialis anterior muscle from both healthy wild-type (WT) muscles (C57BL/10 mice) and dystrophic (mdx mice) muscles (an animal model for human Duchenne muscular dystrophy) before and after contraction-induced injury. A mild in vivo eccentric injury protocol was used due to the high susceptibility of mdx muscles to injury. As expected, mdx mice sustained a greater loss of force (81%) after injury compared with WT (42%). In the uninjured muscles, choline (Cho) levels were 47% lower in the mdx muscles compared with WT muscles. In mdx mice, taurine levels decreased 17%, and Cho levels increased 25% in injured muscles compared with uninjured mdx muscles. Intramyocellular lipids and total muscle lipid levels increased significantly after injury but only in WT. The increase in lipid was confirmed using a permeable lipophilic fluorescence dye. In summary, loss of torque after injury was associated with alterations in muscle metabolite levels that may contribute to the overall injury response in mdx mice. These results show that it is possible to obtain meaningful in vivo (1)H MRS regarding skeletal muscle injury.

  8. Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic beta-cells

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Dela, Flemming

    2005-01-01

    OBJECTIVES: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects......), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naive to antiretroviral therapy (NAIVE) respectively). beta-cell function was evaluated by an intravenous glucose tolerance test. RESULTS: Compared with NONLIPO and NAIVE separately, LIPO displayed markedly reduced ratio...

  9. Redesigned Human Metabolic Simulator

    Science.gov (United States)

    Duffield, Bruce; Jeng, Frank; Lange, Kevin

    2008-01-01

    A design has been formulated for a proposed improved version of an apparatus that simulates atmospheric effects of human respiration by introducing controlled amounts of carbon dioxide, water vapor, and heat into the air. Denoted a human metabolic simulator (HMS), the apparatus is used for testing life-support equipment when human test subjects are not available. The prior version of the HMS, to be replaced, was designed to simulate the respiratory effects of as many as four persons. It exploits the catalytic combustion of methyl acetate, for which the respiratory quotient (the molar ratio of carbon dioxide produced to oxygen consumed) is very close to the human respiratory quotient of about 0.86. The design of the improved HMS provides for simulation of the respiratory effects of as many as eight persons at various levels of activity. The design would also increase safety by eliminating the use of combustion. The improved HMS (see figure) would include a computer that would exert overall control. The computer would calculate the required amounts of oxygen removal, carbon dioxide addition, water addition, and heat addition by use of empirical equations for metabolic profiles of respiration and heat. A blower would circulate air between the HMS and a chamber containing a life-support system to be tested. With the help of feedback from a mass flowmeter, the blower speed would be adjusted to regulate the rate of flow according to the number of persons to be simulated and to a temperature-regulation requirement (the air temperature would indirectly depend on the rate of flow, among other parameters). Oxygen would be removed from the circulating air by means of a commercially available molecular sieve configured as an oxygen concentrator. Oxygen, argon, and trace amounts of nitrogen would pass through a bed in the molecular sieve while carbon dioxide, the majority of nitrogen, and other trace gases would be trapped by the bed and subsequently returned to the chamber. If

  10. Pro-inflammatory macrophages increase in skeletal muscle of high fat-fed mice and correlate with metabolic risk markers in humans

    DEFF Research Database (Denmark)

    Fink, Lisbeth N; Costford, Sheila R; Lee, Yun S

    2014-01-01

    In obesity, immune cells infiltrate adipose tissue. Skeletal muscle is the major tissue of insulin-dependent glucose disposal, and indices of muscle inflammation arise during obesity, but whether and which immune cells increase in muscle remain unclear.......In obesity, immune cells infiltrate adipose tissue. Skeletal muscle is the major tissue of insulin-dependent glucose disposal, and indices of muscle inflammation arise during obesity, but whether and which immune cells increase in muscle remain unclear....

  11. Metabolic demand and muscle damage induced by eccentric cycling of knee extensor and flexor muscles.

    Science.gov (United States)

    Peñailillo, Luis; Guzmán, Nicolás; Cangas, José; Reyes, Alvaro; Zbinden-Foncea, Hermann

    2017-03-01

    The aim of this study was to examine the metabolic demand and extent of muscle damage of eccentric cycling targeting knee flexor (FLEX) and knee extensor (EXT) muscles. Eight sedentary men (23.3 ± 0.7 y) underwent two eccentric cycling sessions (EXT and FLEX) of 30 min each, at 60% of the maximum power output. Oxygen consumption (VO 2 ), heart rate (HR) and rated perceived exertion (RPE) were measured during cycling. Countermovement and squat jumps (CMJ and SJ), muscle flexibility, muscle soreness and pain pressure threshold (PPT) of knee extensor and flexor muscles were measured before, immediately after and 1-4 days after cycling. FLEX showed greater VO 2 (+23%), HR (+14%) and RPE (+18%) than EXT. CMJ and SJ performance decreased similarly after cycling. Muscle soreness increased more after EXT than FLEX and PPT decreased in knee extensor muscles after EXT and decreased in knee flexor muscles after FLEX. Greater loss of muscle flexibility in knee flexor muscles after FLEX was observed. Eccentric cycling of knee flexor muscles is metabolically more demanding than that of knee extensors, however muscle damage induced is similar. Knee flexors experienced greater loss of muscle flexibility possibly due to increased muscle stiffness following eccentric contractions.

  12. Sarcoglycans in human skeletal muscle and human cardiac muscle: a confocal laser scanning microscope study.

    Science.gov (United States)

    Anastasi, G; Cutroneo, G; Trimarchi, F; Rizzo, G; Bramanti, P; Bruschetta, D; Fugazzotto, D; Cinelli, M P; Soscia, A; Santoro, G; Favaloro, A

    2003-01-01

    Sarcoglycans are a subcomplex of transmembrane proteins which are part of the dystrophin-glycoprotein complex. They are expressed in the skeletal, cardiac and smooth muscle. Although numerous studies have been conducted on the sarcoglycan subcomplex in skeletal and cardiac muscle, the manner of the distribution and localization of these proteins along the nonjunctional sarcolemma is not clear. We therefore carried out an indirect immunofluorescence study on surgical biopsies of normal human skeletal muscle and of healthy human atrial myocardium biopsies of patients affected by valvulopathy. Our results indicate that, in skeletal muscle, sarcoglycans have a costameric distribution and all colocalize with each other. Only in a few cases did the alpha-sarcoglycan not colocalize with other sarcoglycans. In addition, these glycoproteins can be localized in different fibers either in the regions of the sarcolemma over band I or band A. In cardiac muscle, our results show a costameric distribution of all proteins examined and, unlike in skeletal muscle, they show a constant colocalization of all sarcoglycans with each other, along with a consistent localization of these proteins in the region of the sarcolemma over band I. In our opinion, this situation seems to confirm the hypothesis of a correlation between the region of the sarcolemma occupied by costameric proteins and the metabolic type, fast or slow, of the muscular fibers. These data, besides opening a new line of research in understanding interactions between the sarcoglycans and other transmembrane proteins, could also be extended to skeletal and cardiac muscles affected by neuromuscular and cardiovascular pathologies to understand possible structural alterations. Copyright 2003 S. Karger AG, Basel

  13. Muscle spindles in the human bulbospongiosus and ischiocavernosus muscles.

    Science.gov (United States)

    Peikert, Kevin; May, Christian Albrecht

    2015-07-01

    Muscle spindles are crucial for neuronal regulation of striated muscles, but their presence and involvement in the superficial perineal muscles is not known. Bulbospongiosus and ischiocavernosus muscle specimens were obtained from 31 human cadavers. Serial sections were stained with hematoxylin and eosin, Sirius red, antibodies against Podocalyxin, myosin heavy chain isoforms (MyHC-slow tonic, S46; MyHC-2a/2x, A4.74), and neurofilament for the purpose of muscle spindle screening, counting, and characterization. A low but consistent number of spindles were detected in both muscles. The muscles contained few intrafusal fibers, but otherwise showed normal spindle morphology. The extrafusal fibers of both muscles were small in diameter. The presence of muscle spindles in bulbospongiosus and ischiocavernosus muscles supports physiological models of pelvic floor regulation and may provide a basis for further clinical observations regarding sexual function and micturition. The small number of muscle spindles points to a minor level of proprioceptive regulation. © 2014 Wiley Periodicals, Inc.

  14. Intracellular compartmentalization of skeletal muscle glycogen metabolism and insulin signalling

    DEFF Research Database (Denmark)

    Prats Gavalda, Clara; Gomez-Cabello, Alba; Vigelsø Hansen, Andreas

    2011-01-01

    The interest in skeletal muscle metabolism and insulin signalling has increased exponentially in recent years as a consequence of their role in the development of type 2 diabetes mellitus. Despite this, the exact mechanisms involved in the regulation of skeletal muscle glycogen metabolism...... and insulin signalling transduction remain elusive. We believe that one of the reasons is that the role of intracellular compartmentalization as a regulator of metabolic pathways and signalling transduction has been rather ignored. This paper briefly reviews the literature to discuss the role of intracellular...... compartmentalization in the regulation of skeletal muscle glycogen metabolism and insulin signalling. As a result, a hypothetical regulatory mechanism is proposed by which cells could direct glycogen resynthesis towards different pools of glycogen particles depending on the metabolic needs. Furthermore, we discuss...

  15. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism.

    Science.gov (United States)

    Gan, Zhenji; Rumsey, John; Hazen, Bethany C; Lai, Ling; Leone, Teresa C; Vega, Rick B; Xie, Hui; Conley, Kevin E; Auwerx, Johan; Smith, Steven R; Olson, Eric N; Kralli, Anastasia; Kelly, Daniel P

    2013-06-01

    The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPARβ/δ was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPARα, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPARβ/δ and PPARα to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPARβ/δ and PPARα participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA (miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor γ (ERRγ). Gain-of-function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERRγ on the expression of miR-499 and miR-208b. This nuclear receptor/miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure.

  16. Satellite cells in human skeletal muscle plasticity.

    Science.gov (United States)

    Snijders, Tim; Nederveen, Joshua P; McKay, Bryon R; Joanisse, Sophie; Verdijk, Lex B; van Loon, Luc J C; Parise, Gianni

    2015-01-01

    Skeletal muscle satellite cells are considered to play a crucial role in muscle fiber maintenance, repair and remodeling. Our knowledge of the role of satellite cells in muscle fiber adaptation has traditionally relied on in vitro cell and in vivo animal models. Over the past decade, a genuine effort has been made to translate these results to humans under physiological conditions. Findings from in vivo human studies suggest that satellite cells play a key role in skeletal muscle fiber repair/remodeling in response to exercise. Mounting evidence indicates that aging has a profound impact on the regulation of satellite cells in human skeletal muscle. Yet, the precise role of satellite cells in the development of muscle fiber atrophy with age remains unresolved. This review seeks to integrate recent results from in vivo human studies on satellite cell function in muscle fiber repair/remodeling in the wider context of satellite cell biology whose literature is largely based on animal and cell models.

  17. Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic beta-cells

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Dela, Flemming

    2005-01-01

    of limb to trunk fat (RLF; > 34%, P insulin sensitivity (> 40%, P 50%, P 50%, P increased clamp free fatty...... acids (P insulin-mediated suppression of lipid oxidation (P insulin sensitivity (r = 0.69), incremental glucose disposal (r = 0.71) and incremental exogenous glucose storage (r = 0.40), all P ...OBJECTIVES: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects...

  18. Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic beta-cells

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Dela, Flemming

    2005-01-01

    OBJECTIVES: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects.......01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P = 0.05) in LIPO compared with the combined groups of NONLIPO and NAIVE, indicating an impaired adaptation of beta-cell function to insulin resistance in LIPO...

  19. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    Human Drug Metabolism, An Introduction, Second Edition provides an accessible introduction to the subject and will be particularly invaluable to those who already have some understanding of the life sciences...

  20. Insights into the regulation of muscle metabolism and growth in mice and hibernating grizzly bears

    OpenAIRE

    Mugahid (Megahed), Douaa (Doaa)

    2015-01-01

    Mechanotransduction plays an important role in the regulation of muscle growth and metabolic signalling in striated muscle. Muscle disuse reduces mechanical input to the muscle, which results in a loss of muscle mass. Here I describe how titin's mechanically activated kinase domain affects muscle growth and metabolism via p62 and Akt signalling. I also demonstrate how changes in metabolic and growth signalling in hibernating grizzly bear help maintain muscle mass under conditio...

  1. Effects of anabolic hormones on structural, metabolic and functional aspects of skeletal muscle

    Directory of Open Access Journals (Sweden)

    Flávio de Oliveira Pires

    2009-06-01

    Full Text Available This study reviewed information regarding the effects of anabolic hormones on strength gain and muscle hypertrophy, emphasizing the physiological mechanisms that may increase muscle strength. Structural, metabolic and functional aspects were analyzed and special attention was paid to the dose-response relationship. The Pubmed database was searched and studies were selected according to relevance and date of publication (last 15 years. The administration of high testosterone doses (~600 mg/week potentiates the effects of strength training, increasing lean body mass, muscle fiber type IIA and IIB cross-sectional area, and the number of myonuclei. There is no evidence of conversion between MHC isoforms. The interaction between testosterone administration and strength training seems to modify some metabolic pathways, increasing protein synthesis, glycogen and ATP-CP muscle stores and improving fat mobilization. Changes in 17-estradiol concentration or in the ACTH-cortisol and insulin-glucagon ratios seem to be associated with these metabolic alterations. Regarding performance, testosterone administration may improve muscle strength by 5-20% depending on the dose used. On the other hand, the effects of growth hormone on the structural and functional aspects of skeletal muscle are not evident, with this hormone more affecting metabolic aspects. However, strictly controlled human studies are necessary to establish the extent of the effects of anabolic hormones on structural, metabolic and functional aspects.

  2. Muscle metabolic remodelling in response to endurance exercise in salmonids

    Directory of Open Access Journals (Sweden)

    Andrea J Morash

    2014-11-01

    Full Text Available Phenotypic plasticity of skeletal muscle is relevant to swimming performance and metabolism in fishes, especially those that undergo extreme locomotory feats, such as seasonal migration. However, the influence of endurance exercise and the molecular mechanisms coordinating this remodelling are not well understood. The present study examines muscle metabolic remodelling associated with endurance exercise in fed rainbow trout as compared to migrating salmon. Trout were swum for 4 weeks at 1.5BL/s, a speed similar to that of migrating salmon and red and white muscles were sampled after each week. We quantified changes in key enzymes in aerobic and carbohydrate metabolism (citrate synthase (CS, β-hydroxyacyl-CoA dehydrogenase (HOAD, hexokinase (HK and changes in mRNA expression of major regulators of metabolic phenotype (AMPK, PPARs and lipid (carnitine palmitoyltransferase, CPT I, protein (aspartate aminotransferase, AST and carbohydrate (HK oxidation pathways. After one week of swimming substantial increases were seen in AMPK and PPARα mRNA expression and of their downstream target genes, CPTI and HK in red muscle. However, significant changes in CS and HK activity occurred only after 4 weeks. In contrast, there were few changes in mRNA expression and enzyme activities in white muscle over the 4-weeks. Red muscle results mimic those found in migrating salmon suggesting a strong influence of exercise on red muscle phenotype. In white muscle, only changes in AMPK and PPAR expression were similar to that seen with migrating salmon. However, in contrast to exercise alone, in natural migration HK decreased while AST increased suggesting that white muscle plays a role in supplying fuel and intermediates possibly through tissue breakdown during prolonged fasting. Dissecting individual and potentially synergistic effects of multiple stressors will enable us to determine major drivers of the metabolic phenotype and their impacts on whole animal

  3. Metabolism of phthalates in humans

    DEFF Research Database (Denmark)

    Frederiksen, Hanne; Skakkebaek, Niels E; Andersson, Anna-Maria

    2007-01-01

    on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some...... phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate...

  4. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock

    DEFF Research Database (Denmark)

    Dyar, Kenneth A.; Ciciliot, Stefano; Wright, Lauren E.

    2014-01-01

    Circadian rhythms control metabolism and energy homeostasis, but the role of the skeletal muscle clock has never been explored. We generated conditional and inducible mouse lines with muscle-specific ablation of the core clock gene Bmal1. Skeletal muscles from these mice showed impaired insulin......-stimulated glucose uptake with reduced protein levels of GLUT4, the insulin-dependent glucose transporter, and TBC1D1, a Rab-GTPase involved in GLUT4 translocation. Pyruvate dehydrogenase (PDH) activity was also reduced due to altered expression of circadian genes Pdk4 and Pdp1, coding for PDH kinase and phosphatase......, respectively. PDH inhibition leads to reduced glucose oxidation and diversion of glycolytic intermediates to alternative metabolic pathways, as revealed by metabolome analysis. The impaired glucose metabolism induced by muscle-specific Bmal1 knockout suggests that a major physiological role of the muscle clock...

  5. Respiratory muscle strength and muscle endurance are not affected by acute metabolic acidemia.

    NARCIS (Netherlands)

    Nizet, T.A.C.; Heijdra, Y.F.; Elshout, F.J.J. van den; Ven, M.J.T. van de; Bosch, F.H.; Mulder, P.H.M. de; Folgering, H.T.M.

    2009-01-01

    Respiratory muscle fatigue in asthma and chronic obstructive lung disease (COPD) contributes to respiratory failure with hypercapnia, and subsequent respiratory acidosis. Therapeutic induction of acute metabolic acidosis further increases the respiratory drive and, therefore, may diminish

  6. Associations of Sarcopenia and Sarcopenic Obesity With Metabolic Syndrome Considering Both Muscle Mass and Muscle Strength

    Science.gov (United States)

    2016-01-01

    Objectives: We investigated the associations of sarcopenia-defined both in terms of muscle mass and muscle strength-and sarcopenic obesity with metabolic syndrome. Methods: Secondary data pertaining to 309 subjects (85 men and 224 women) were collected from participants in exercise programs at a health center in a suburban area. Muscle mass was measured using bioelectrical impedance analysis, and muscle strength was measured via handgrip strength. Sarcopenia based on muscle mass alone was defined as a weight-adjusted skeletal muscle mass index more than two standard deviations below the mean of a sex-specific young reference group (class II sarcopenia). Two cut-off values for low handgrip strength were used: the first criteria were sarcopenia and being in the two highest quintiles of total body fat percentage among the subjects. The associations of sarcopenia and sarcopenic obesity with metabolic syndrome were evaluated using logistic regression models. Results: The age-adjusted risk ratios (RRs) of metabolic syndrome being compared in people with or without sarcopenia defined in terms of muscle mass were 1.25 (95% confidence interval [CI], 1.06 to 1.47, p=0.008) in men and 1.12 (95% CI, 1.06 to 1.19, psarcopenia defined in terms of muscle mass and sarcopenic obesity with metabolic syndrome were statistically significant in both men and women. Therefore, sarcopenia and sarcopenic obesity must be considered as part of the community-based management of non-communicable diseases. PMID:26841883

  7. Aging, metabolism and stem cells: Spotlight on muscle stem cells.

    Science.gov (United States)

    García-Prat, Laura; Muñoz-Cánoves, Pura

    2017-04-15

    All tissues and organs undergo a progressive regenerative decline as they age. This decline has been mainly attributed to loss of stem cell number and/or function, and both stem cell-intrinsic changes and alterations in local niches and/or systemic environment over time are known to contribute to the stem cell aging phenotype. Advancing in the molecular understanding of the deterioration of stem cell cells with aging is key for targeting the specific causes of tissue regenerative dysfunction at advanced stages of life. Here, we revise exciting recent findings on why stem cells age and the consequences on tissue regeneration, with a special focus on regeneration of skeletal muscle. We also highlight newly identified common molecular pathways affecting diverse types of aging stem cells, such as altered proteostasis, metabolism, or senescence entry, and discuss the questions raised by these findings. Finally, we comment on emerging stem cell rejuvenation strategies, principally emanating from studies on muscle stem cells, which will surely burst tissue regeneration research for future benefit of the increasing human aging population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. In utero undernutrition programs skeletal and cardiac muscle metabolism

    Directory of Open Access Journals (Sweden)

    Brittany eBeauchamp

    2016-01-01

    Full Text Available In utero undernutrition is associated with increased risk for insulin resistance, obesity, and cardiovascular disease during adult life. A common phenotype associated with low birth weight is reduced skeletal muscle mass. Given the central role of skeletal muscle in whole body metabolism, alterations in its mass as well as its metabolic characteristics may contribute to disease risk. This review highlights the metabolic alterations in cardiac and skeletal muscle associated with in utero undernutrition and low birth weight. These tissues have high metabolic demands and are known to be sites of major metabolic dysfunction in obesity, type 2 diabetes, and cardiovascular disease. Recent research demonstrates that mitochondrial energetics are decreased in skeletal and cardiac muscles of adult offspring from undernourished mothers. These effects apparently lead to the development of a thrifty phenotype, which may represent overall a compensatory mechanism programmed in utero to handle times of limited nutrient availability. However, in an environment characterized by food abundance, the effects are maladaptive and increase adulthood risks of metabolic disease.

  9. Sarcoglycan subcomplex in normal and pathological human muscle fibers.

    Science.gov (United States)

    Anastasi, G; Cutroneo, G; Rizzo, G; Favaloro, A

    2007-01-01

    Sarcoglycans are a sub-complex of transmembrane proteins which are part of the dystrophin-glycoprotein complex (DGC). They are expressed above all in the skeletal, cardiac and smooth muscle. Although numerous studies have been conducted on the sarcoglycan sub-complex in skeletal and cardiac muscle, the manner of distribution and localization of these proteins along the non-junctional sarcolemma is still not clear. Furthermore, there are unclear data about the actual role of sarcoglycans in human skeletal muscle affected by sarcoglycanopathies. In our studies on human skeletal muscle, normal and pathological, we determined the localization, distribution and interaction of these glycoproteins. Our results, on normal human skeletal muscle, showed that the sarcoglycans can be localized both in the region of the sarcolemma over the I band and over the A band, hypothesizing a correlation between regions of the sarcolemma occupied by costameres and the metabolic type of the fibers (slow and fast). Our data on skeletal muscle affected by sarcoglycanopathy confirmed the hypothesis of a bidirectional signaling between sarcoglycans and integrins and the interaction of filamin2 with both sarcoglycans and integrins. In addition, we have recently demonstrated, in smooth muscle, the presence of alpha-SG, in contrast with data of other Authors. Finally, we analyzed the association between contractile activity and quantitative correlation between alpha- and epsilon-SG, in order to better define the arrangement of sarcoglycan subcomplex.

  10. Human skeletal muscle xenograft as a new preclinical model for muscle disorders.

    Science.gov (United States)

    Zhang, Yuanfan; King, Oliver D; Rahimov, Fedik; Jones, Takako I; Ward, Christopher W; Kerr, Jaclyn P; Liu, Naili; Emerson, Charles P; Kunkel, Louis M; Partridge, Terence A; Wagner, Kathryn R

    2014-06-15

    Development of novel therapeutics requires good animal models of disease. Disorders for which good animal models do not exist have very few drugs in development or clinical trial. Even where there are accepted, albeit imperfect models, the leap from promising preclinical drug results to positive clinical trials commonly fails, including in disorders of skeletal muscle. The main alternative model for early drug development, tissue culture, lacks both the architecture and, usually, the metabolic fidelity of the normal tissue in vivo. Herein, we demonstrate the feasibility and validity of human to mouse xenografts as a preclinical model of myopathy. Human skeletal muscle biopsies transplanted into the anterior tibial compartment of the hindlimbs of NOD-Rag1(null) IL2rγ(null) immunodeficient host mice regenerate new vascularized and innervated myofibers from human myogenic precursor cells. The grafts exhibit contractile and calcium release behavior, characteristic of functional muscle tissue. The validity of the human graft as a model of facioscapulohumeral muscular dystrophy is demonstrated in disease biomarker studies, showing that gene expression profiles of xenografts mirror those of the fresh donor biopsies. These findings illustrate the value of a new experimental model of muscle disease, the human muscle xenograft in mice, as a feasible and valid preclinical tool to better investigate the pathogenesis of human genetic myopathies and to more accurately predict their response to novel therapeutics. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men

    DEFF Research Database (Denmark)

    Olesen, Jesper; Gliemann Hybholt, Lasse; Biensøe, Rasmus S

    2014-01-01

    Aim: To investigate the metabolic and anti-inflammatory effects of resveratrol alone and when combined with exercise training in skeletal muscle of aged human subjects. Material and Methods: Healthy physically inactive men (60-72 year old) were randomized into either 8 weeks of daily intake of 25...

  12. Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.

    Science.gov (United States)

    Lerin, Carles; Goldfine, Allison B; Boes, Tanner; Liu, Manway; Kasif, Simon; Dreyfuss, Jonathan M; De Sousa-Coelho, Ana Luisa; Daher, Grace; Manoli, Irini; Sysol, Justin R; Isganaitis, Elvira; Jessen, Niels; Goodyear, Laurie J; Beebe, Kirk; Gall, Walt; Venditti, Charles P; Patti, Mary-Elizabeth

    2016-10-01

    Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear. To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding. Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.

  13. Potentiation of cGMP signaling increases oxygen delivery and oxidative metabolism in contracting skeletal muscle of older but not young humans

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Piil, Peter Bergmann; Egelund, Jon

    2015-01-01

    Aging is associated with progressive loss of cardiovascular and skeletal muscle function. The impairment in physical capacity with advancing age could be related to an insufficient peripheral O2 delivery to the exercising muscles. Furthermore, the mechanisms underlying an impaired blood flow regu...

  14. Liver and muscle protein metabolism in cachexia

    NARCIS (Netherlands)

    Peters, J.A.C.

    2009-01-01

    Up to 50% of cancer patients suffer from progressive weight loss (cachexia). Cachexia is induced by proinflammatory mediators (cytokines), induced by the tumor’s presence. These cytokines induce so-called acute phase protein synthesis by the liver, followed by skeletal muscle protein breakdown.

  15. The Human Skeletal Muscle Proteome Project

    DEFF Research Database (Denmark)

    Gonzalez-Freire, Marta; Semba, Richard D.; Ubaida-Mohien, Ceereena

    2017-01-01

    Skeletal muscle is a large organ that accounts for up to half the total mass of the human body. A progressive decline in muscle mass and strength occurs with ageing and in some individuals configures the syndrome of ‘sarcopenia’, a condition that impairs mobility, challenges autonomy, and is a risk...... factor for mortality. The mechanisms leading to sarcopenia as well as myopathies are still little understood. The Human Skeletal Muscle Proteome Project was initiated with the aim to characterize muscle proteins and how they change with ageing and disease. We conducted an extensive review...... for the identification and quantification of proteins in skeletal muscle to discover new mechanisms for sarcopenia and specific muscle diseases that can be targeted for the prevention and treatment....

  16. Human skeletal muscle releases leptin in vivo

    DEFF Research Database (Denmark)

    Wolsk, Emil; Grøndahl, Thomas Sahl; Pedersen, Bente Klarlund

    2012-01-01

    Leptin is considered an adipokine, however, cultured myocytes have also been found to release leptin. Therefore, as proof-of-concept we investigated if human skeletal muscle synthesized leptin by measuring leptin in skeletal muscle biopsies. Following this, we quantified human skeletal muscle...... and adipose tissue leptin release in vivo. We recruited 16 healthy male human participants. Catheters were inserted into the femoral artery and vein draining skeletal muscle, as well as an epigastric vein draining the abdominal subcutaneous adipose tissue. By combining the veno-arterial differences in plasma...... leptin with measurements of blood flow, leptin release from both tissues was quantified. To induce changes in leptin, the participants were infused with either saline or adrenaline in normo-physiological concentrations. The presence of leptin in skeletal muscle was confirmed by western blotting. Leptin...

  17. Effect of muscle acidity on muscle metabolism and fatigue during intense exercise in man

    DEFF Research Database (Denmark)

    Bangsbo, Jens; Madsen, K.; Kiens, Bente

    1996-01-01

    1. The aim of this study was to examine the effect of muscle pH on muscle metabolism and development of fatigue during intense exercise. 2. Seven subjects performed intense exhaustive leg exercise on two occasions: with and without preceding intense intermittent arm exercise leading to high...... (kg wet weight)-1 min-1). The rate of muscle glycogen breakdown was the same in C and HL (8.1 +/- 1.2 vs. 8.2 +/- 1.0 mmol (kg wet weight)-1 min-1). 5. The present data suggest that elevated muscle acidity does not reduce muscle glycogenolysis/glycolysis and is not the only cause of fatigue during...... intense exercise in man. Instead, accumulation of potassium in muscle interstitium may be an important factor in the development of fatigue....

  18. Metabolic adaptation of skeletal muscles to gravitational unloading

    Science.gov (United States)

    Ohira, Y.; Yasui, W.; Kariya, F.; Wakatsuki, T.; Nakamura, K.; Asakura, T.; Edgerton, V. R.

    Responses of high-energy phosphates and metabolic properties to hindlimb suspension were studied in adult rats. The relative content of phosphocreatine (PCr) in the calf muscles was significantly higher in rats suspended for 10 days than in age-matched cage controls. The Pi/PCr ratio, where Pi is inorganic phosphate, in suspended muscles was less than controls. The absolute weights of soleus and medial gastrocnemius (MG) were approximately 40% less than controls. Although the % fiber distribution in MG was unchanged, the % slow fibers decreased and the % fibers which were classified as both slow and fast was increased in soleus. The activities (per unit weight or protein) of succinate dehydrogenase and lactate dehydrogenase in soleus were unchanged but those of cytochrome oxidase, β-hydroxyacyl CoA dehydrogenase, and citrate synthase were decreased following unloading. None of these enzyme activities in MG changed. However, the total levels of all enzymes in whole muscles decreased by suspension. It is suggested that shift of slow muscle toward fast type by unloading is associated with a decrease in mitochondrial biogenesis. Further, gravitational unloading affected the levels of muscle proteins differently even in the same mitochondrial enzymes. Unloading-related atrophy is prominent in red muscle or slow-twitch fiber 1, 2. Such atrophy is accompanied by a shift of contractile properties toward fast-twitch type 2-9. Further, inhibition of mitochondrial metabolism in these muscles is also reported by some studies 10-14 suggesting a lowered mitochondrial biogenesis, although results from some studies do not necessarily agree 1, 7, 15. However, the precise mechanism responsible for such alterations of muscle properties in response to gravitational unloading is unclear. On the contrary, mitochondrial biogenesis, suggested by mitochondrial enzyme activities and/or mass, is stimulated in muscles with depleted high-energy phosphates by cold exposure 16 and/or by feeding

  19. Metabolism of phthalates in humans

    DEFF Research Database (Denmark)

    Frederiksen, Hanne; Skakkebaek, Niels E; Andersson, Anna-Maria

    2007-01-01

    Phthalates are synthetic compounds widely used as plasticisers, solvents and additives in many consumer products. Several animal studies have shown that some phthalates possess endocrine disrupting effects. Some of the effects of phthalates seen in rats are due to testosterone lowering effects...... on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some...... phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate...

  20. Human metabolism of caesium

    Energy Technology Data Exchange (ETDEWEB)

    Raeaef, C.L. [Lund Univ., Dept. of Radiation Physics in Malmoe (Sweden); Falk, R. [Swedish Radiation Protection Authority (Sweden); Lauridsen, Bente [Risoe National Lab. (Denmark); Rahola, T. [STUK - Radiation and Nuclear Safety Authority (Finland); Soogard-Hansen, J. [NRPA - Norwegian Radiation Protection Authority (Norway)

    2006-04-15

    A study of the human biokinetics of caesium in two forms, i.) incorporated in foodstuff (137Cs in perch and mushrooms) and ii.) in ionic state ({sup 134}Cs in aqueous solution) has been carried out at the department of Radiation Physics in Malmoe, starting in 2001. The results of the pilot study were published in 2004, and a continuation of that study has now been carried out by means of NKS funding (NKS-B Cskinetik). The aim is to, i.) investigate whether Scandinavian populations exhibit shorter biological half-time of radiocaesium than other populations; ii.) extend the biokinetic study to additional human subjects from the other Nordic countries. Results from the continued study further indicate a near complete absorption of radiocaesium in the gastro-intestinal tract, be it in ion state or contained in food matrix. So far, the literature survey of Nordic studies on biokinetics of Cs suggests that the biological half time is somewhat shorter among Scandinavian males (84 days vs. ICRP-value of 110 days), although females do not exhibit any significant difference (64 days vs ICRP value of 65 days). (au)

  1. Dysfunctional muscle and liver glycogen metabolism in mdx dystrophic mice.

    Science.gov (United States)

    Stapleton, David I; Lau, Xianzhong; Flores, Marcelo; Trieu, Jennifer; Gehrig, Stefan M; Chee, Annabel; Naim, Timur; Lynch, Gordon S; Koopman, René

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD patients and mdx mice (an animal model of DMD) exhibit altered metabolic disturbances that cannot be attributed to the loss of dystrophin directly. We tested the hypothesis that glycogen metabolism is defective in mdx dystrophic mice. Dystrophic mdx mice had increased skeletal muscle glycogen (79%, (Pglycogen synthesis is initiated by glycogenin, the expression of which was increased by 50% in mdx mice (PGlycogen synthase activity was 12% higher (Pglycogen branching enzyme activity was 70% lower (Pglycogen breakdown, glycogen phosphorylase, had 62% lower activity (Pglycogen debranching enzyme expression was 50% higher (Pglycogen (Pglycogen metabolism in mdx mice identified reduced glycogenin protein expression (46% less; Pglycogen but reduced amounts of liver glycogen.

  2. Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness

    DEFF Research Database (Denmark)

    Bozek, Katarzyna; Wei, Yuning; Yan, Zheng

    2014-01-01

    Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees......, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy...... metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized...

  3. Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness.

    Directory of Open Access Journals (Sweden)

    Katarzyna Bozek

    2014-05-01

    Full Text Available Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys.

  4. Exceptional Evolutionary Divergence of Human Muscle and Brain Metabolomes Parallels Human Cognitive and Physical Uniqueness

    Science.gov (United States)

    Bozek, Katarzyna; Wei, Yuning; Yan, Zheng; Liu, Xiling; Xiong, Jieyi; Sugimoto, Masahiro; Tomita, Masaru; Pääbo, Svante; Pieszek, Raik; Sherwood, Chet C.; Hof, Patrick R.; Ely, John J.; Steinhauser, Dirk; Willmitzer, Lothar; Bangsbo, Jens; Hansson, Ola; Call, Josep; Giavalisco, Patrick; Khaitovich, Philipp

    2014-01-01

    Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys. PMID:24866127

  5. Regulatory role of leptin in glucose and lipid metabolism in skeletal muscle

    Directory of Open Access Journals (Sweden)

    Yasuhiko Minokoshi

    2012-01-01

    Full Text Available Leptin is a hormone secreted by adipocytes that plays a pivotal role in regulation of food intake, energy expenditure, and neuroendocrine function. Several lines of evidences indicate that independent of the anorexic effect, leptin regulates glucose and lipid metabolism in peripheral tissues in rodents and humans. It has been shown that leptin improves the diabetes phenotype in lipodystrophic patients and rodents. Moreover, leptin suppresses the development of severe, progressive impairment of glucose metabolism in insulin-deficient diabetes in rodents. We found that leptin increases glucose uptake and fatty acid oxidation in skeletal muscle in rats and mice in vivo. Leptin increases glucose uptake in skeletal muscle via the hypothalamic-sympathetic nervous system axis and β-adrenergic mechanism, while leptin stimulates fatty acid oxidation in muscle via AMP-activated protein kinase (AMPK. Leptin-induced fatty acid oxidation results in the decrease of lipid accumulation in muscle, which can lead to functional impairments called as "lipotoxicity." Activation of AMPK occurs by direct action of leptin on muscle and through the medial hypothalamus-sympathetic nervous system and α-adrenergic mechanism. Thus, leptin plays an important role in the regulation of glucose and fatty acid metabolism in skeletal muscle.

  6. Role of SERCA Pump in Muscle Thermogenesis and Metabolism.

    Science.gov (United States)

    Periasamy, Muthu; Maurya, Santosh Kumar; Sahoo, Sanjaya Kumar; Singh, Sushant; Sahoo, Sanjaya Kumar; Reis, Felipe C G; Bal, Naresh Chandra

    2017-06-18

    In muscle cells, the sarcoplasmic reticulum (SR) not only acts as a Ca2+ store, but also regulates the contractile characteristics of the muscle. Ca2+ release from the SR is the primary mechanism for activating muscle contraction and reuptake of Ca2+ by the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump causes muscle relaxation. The SERCA pump isoforms are encoded by three genes, SERCA 1, 2, and 3, which are differentially expressed in muscle and determine SR Ca2+ dynamics by affecting the rate and amount of Ca2+ uptake, thereby affecting SR store and release of Ca2+ in muscle. In muscle, small molecular weight proteins, including Phospholamban (PLB) and Sarcolipin (SLN), also regulate the SERCA pump. Regulation of the SERCA pump by PLB or SLN affects cytosolic Ca2+ dynamics and changes in cytosolic Ca2+ not only affect contractile function, but also mitochondrial ATP production. Recent studies have shown that alterations in cytosolic Ca2+ affects Ca2+ entry into mitochondria and ATP production; thus, Ca2+ serves as an integrating signal between muscle contraction-dependent energy demand and mitochondrial energy production. In addition, changes in cytosolic Ca2+ can affect Ca2+ signaling pathways modulating gene expression and muscle growth. An emerging area of research shows that SR Ca2+ cycling is also a player in muscle-based nonshivering thermogenesis. Recent data shows that SERCA uncoupling by SLN leads to increased ATP hydrolysis and heat production. Our studies, using genetically altered mouse models of SLN, show that SLN/SERCA interaction plays an important role in muscle thermogenesis and metabolism, which will be discussed here, in great length. © 2017 American Physiological Society. Compr Physiol 7:879-890, 2017. Copyright © 2017 John Wiley & Sons, Inc.

  7. Protein and amino acid metabolism in skeletal muscle

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Guoyao.

    1989-01-01

    Isolated chick extensor digitorum communis (EDC) muscles and, in some experiments, rat skeletal muscles were used to study a number of aspects of protein and amino acid metabolism. (1) Chick EDC muscles synthesize and release large amounts of alanine and glutamine, which indirectly obtain their amino groups from branched-chain amino acids (BCAA). (2) Acetoacetate or DL-{beta}-hydroxybutyrate (4 mM) decrease (P < 0.01) alanine synthesis and BCAA transamination in EDC muscles from 24-h fasted chicks by decreasing (P < 0.01) intracellular concentrations of pyruvate due to inhibition of glycolysis. (3) Glutamine is extensively degraded in skeletal muscles from both chicks and rats, thus challenging the traditional view that glutamine oxidation is negligible in skeletal muscle. The cytosolic glutamine aminotransferases L and K in the rat and the mitochondrial phosphate-activated glutaminase in the chick play important roles in the conversion of glutamine to {alpha}-ketoglutarate for further oxidation. (4) Although methionine has been reported to be extensively transaminated in rat skeletal muscle preparations in the absence of other amino acids, transamination of methionine is absent or negligible in chick and rat skeletal muscles in the presence of physiological concentrations of amino acids. (5) Glutamine at 1.0-15 mM increases (P < 0.01) protein synthesis ({sup 3}H-phenylalanine incorporation), and at 10.0-15.0 mM decreases (P < 0.05) protein degradation ({sup 3}H-phenylalanine release from prelabelled protein in vivo) in EDC muscles from fed chicks as compared to muscles incubated in the absence of glutamine. (6) Acetoacetate or DL-{beta}-hydroxybutyrate (4 mM) has a small but significant inhibitory effect (P < 0.05) on the rate of protein synthesis, but has no effect (P > 0.05) on the rate of protein degradation in EDC muscles from fed chicks.

  8. Skeletal muscle metabolism during prolonged exercise in Pompe disease

    DEFF Research Database (Denmark)

    Preisler, Nicolai; Laforêt, Pascal; Madsen, Karen Lindhardt

    2017-01-01

    of exercise, it is important in Pompe disease to acquire more information about muscle substrate use during exercise. METHODS: Seven adults with Pompe disease were matched to a healthy control group (1:1). We determined (1) peak oxidative capacity (VO2peak) and (2) carbohydrate and fatty acid metabolism...... = 0.318) and mean difference 0.016 µmol/kg/min (CI: 1.287 to -1.255, P = 0.710), respectively). CONCLUSION: Reflecting muscle weakness and wasting, Pompe disease is associated with markedly reduced maximal exercise capacity. However, glycogenolysis is not impaired in exercise. Unlike in other...... metabolic myopathies, skeletal muscle substrate use during exercise is normal in Pompe disease rendering exercise less complicated for e.g. medical or recreational purposes....

  9. Searching for proprioceptors in human facial muscles.

    Science.gov (United States)

    Cobo, Juan L; Abbate, Francesco; de Vicente, Juan C; Cobo, Juan; Vega, José A

    2017-02-15

    The human craniofacial muscles innervated by the facial nerve typically lack muscle spindles. However these muscles have proprioception that participates in the coordination of facial movements. A functional substitution of facial proprioceptors by cutaneous mechanoreceptors has been proposed but at present this alternative has not been demonstrated. Here we have investigated whether other kinds of sensory structures are present in two human facial muscles (zygomatic major and buccal). Human checks were removed from Spanish cadavers, and processed for immunohistochemical detection of nerve fibers (neurofilament proteins and S100 protein) and two putative mechanoproteins (acid-sensing ion channel 2 and transient receptor potential vanilloid 4) associated with mechanosensing. Nerves of different calibers were found in the connective septa and within the muscle itself. In all the muscles analysed, capsular corpuscle-like structures resembling elongated or round Ruffini-like corpuscles were observed. Moreover the axon profiles within these structures displayed immunoreactivity for both putative mechanoproteins. The present results demonstrate the presence of sensory structures in facial muscles that can substitute for typical muscle spindles as the source of facial proprioception. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Metabolic hypothesis for human altriciality.

    Science.gov (United States)

    Dunsworth, Holly M; Warrener, Anna G; Deacon, Terrence; Ellison, Peter T; Pontzer, Herman

    2012-09-18

    The classic anthropological hypothesis known as the "obstetrical dilemma" is a well-known explanation for human altriciality, a condition that has significant implications for human social and behavioral evolution. The hypothesis holds that antagonistic selection for a large neonatal brain and a narrow, bipedal-adapted birth canal poses a problem for childbirth; the hominin "solution" is to truncate gestation, resulting in an altricial neonate. This explanation for human altriciality based on pelvic constraints persists despite data linking human life history to that of other species. Here, we present evidence that challenges the importance of pelvic morphology and mechanics in the evolution of human gestation and altriciality. Instead, our analyses suggest that limits to maternal metabolism are the primary constraints on human gestation length and fetal growth. Although pelvic remodeling and encephalization during hominin evolution contributed to the present parturitional difficulty, there is little evidence that pelvic constraints have altered the timing of birth.

  11. Studies of gene expression and activity of hexokinase, phosphofructokinase and glycogen synthase in human skeletal muscle in states of altered insulin-stimulated glucose metabolism

    DEFF Research Database (Denmark)

    Vestergaard, H

    1999-01-01

    with disorders characterized by insulin resistance like non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) before and after therapeutic interventions, patients with microvascular angina and patients with severe insulin resistant diabetes mellitus and congenital muscle......When whole body insulin-stimulated glucose disposal rate is measured in man applying the euglycaemic, hyperinsulinaemic clamp technique it has been shown that approximately 75% of glucose is taken up by skeletal muscle. After the initial transport step, glucose is rapidly phosphorylated to glucose......-6-phosphate and routed into the major pathways of either glucose storage as glycogen or the glycolytic/tricarboxylic acid pathway. Glucose uptake in skeletal muscle involves-the activity of specific glucose transporters and hexokinases, whereas, phosphofructokinase and glycogen synthase hold...

  12. Esterase profile of human masseter muscle

    DEFF Research Database (Denmark)

    Kirkeby, S; Moe, D; Vilmann, H

    1988-01-01

    The esterase profile of fresh human masseter muscle was investigated by use of histochemistry and electrophoresis. The histochemical methods included reactions for alpha-naphthyl esterase, myofibrillar ATPase, reverse myofibrillar ATPase and succinic dehydrogenase. In frozen sections of the muscle......C. iM and Type II A fibres showed a moderate esterase reaction and Type II B fibres had a low activity. The electrophoretic gels stained for esterase activity showed that the human masseter muscle possesses a slow migrating double band with high enzyme activity and a cascade of faster migrating...

  13. Induction of GLUT-1 protein in adult human skeletal muscle fibers

    DEFF Research Database (Denmark)

    Gaster, M; Franch, J; Staehr, P

    2000-01-01

    Prompted by our recent observations that GLUT-1 is expressed in fetal muscles, but not in adult muscle fibers, we decided to investigate whether GLUT-1 expression could be reactivated. We studied different stimuli concerning their ability to induce GLUT-1 expression in mature human skeletal muscle...... fibers. Metabolic stress (obesity, non-insulin-dependent diabetes mellitus), contractile activity (training), and conditions of de- and reinnervation (amyotrophic lateral sclerosis) could not induce GLUT-1 expression in human muscle fibers. However, regenerating muscle fibers in polymyositis expressed...... GLUT-1. In contrast to GLUT-1, GLUT-4 was expressed in all investigated muscle fibers. Although the significance of GLUT-1 in adult human muscle fibers appears limited, GLUT-1 may be of importance for the glucose supplies in immature and regenerating muscle....

  14. Recurring adaptation effect on energy metabolism of atrophic shin muscles

    Directory of Open Access Journals (Sweden)

    Afanasyev М.А.

    2012-06-01

    Full Text Available The article is devoted to recurring adaptation effect on energy metabolism of atrophic shin muscles. The purpose: Investigation of markers of activity of muscular fibers of gravitation-dependent muscles in condition of early posthypoki-netic readaptation. Materials. Muscles-antagonists have been taken from the shin area of hind limbs of a rat. Methods. Immunohistochemical dyeing of myofibrils of different type (I and II on glycogen and triglycerides have been used. Results. We have revealed dynamic changes of the endocellular contents of researched energy substrata on different terms of the period of posthypokinetic restoration. Conclusion. Investigated substrata my serve as adequate functional markers of muscles in the conditions under the study

  15. Satellite cells in human skeletal muscle plasticity

    Directory of Open Access Journals (Sweden)

    Tim eSnijders

    2015-10-01

    Full Text Available Skeletal muscle satellite cells are considered to play a crucial role in muscle fiber maintenance, repair and remodelling. Our knowledge of the role of satellite cells in muscle fiber adaptation has traditionally relied on in vitro cell and in vivo animal models. Over the past decade, a genuine effort has been made to translate these results to humans under physiological conditions. Findings from in vivo human studies suggest that satellite cells play a key role in skeletal muscle fiber repair/remodelling in response to exercise. Mounting evidence indicates that aging has a profound impact on the regulation of satellite cells in human skeletal muscle. Yet, the precise role of satellite cells in the development of muscle fiber atrophy with age remains unresolved. This review seeks to integrate recent results from in vivo human studies on satellite cell function in muscle fiber repair/remodelling in the wider context of satellite cell biology whose literature is largely based on animal and cell models.

  16. Muscle Carnosine Is Associated with Cardiometabolic Risk Factors in Humans.

    Directory of Open Access Journals (Sweden)

    Barbora de Courten

    Full Text Available Carnosine is a naturally present dipeptide abundant in skeletal muscle and an over-the counter food additive. Animal data suggest a role of carnosine supplementation in the prevention and treatment of obesity, insulin resistance, type 2 diabetes and cardiovascular disease but only limited human data exists.Samples of vastus lateralis muscle were obtained by needle biopsy. We measured muscle carnosine levels (high-performance liquid chromatography, % body fat (bioimpedance, abdominal subcutaneous and visceral adiposity (magnetic resonance imaging, insulin sensitivity (euglycaemic hyperinsulinemic clamp, resting energy expenditure (REE, indirect calorimetry, free-living ambulatory physical activity (accelerometers and lipid profile in 36 sedentary non-vegetarian middle aged men (45±7 years with varying degrees of adiposity and glucose tolerance. Muscle carnosine content was positively related to % body fat (r = 0.35, p = 0.04 and subcutaneous (r = 0.38, p = 0.02 but not visceral fat (r = 0.17, p = 0.33. Muscle carnosine content was inversely associated with insulin sensitivity (r = -0.44, p = 0.008, REE (r = -0.58, p<0.001 and HDL-cholesterol levels (r = -0.34, p = 0.048. Insulin sensitivity and physical activity were the best predictors of muscle carnosine content after adjustment for adiposity.Our data shows that higher carnosine content in human skeletal muscle is positively associated with insulin resistance and fasting metabolic preference for glucose. Moreover, it is negatively associated with HDL-cholesterol and basal energy expenditure. Intervention studies targeting insulin resistance, metabolic and cardiovascular disease risk factors are necessary to evaluate its putative role in the prevention and management of type 2 diabetes and cardiovascular disease.

  17. Low muscle fitness is associated with metabolic risk in youth.

    Science.gov (United States)

    Steene-Johannessen, Jostein; Anderssen, Sigmund A; Kolle, Elin; Andersen, Lars B

    2009-07-01

    To examine the independent associations of muscle fitness and cardiorespiratory fitness with clustered metabolic risk in youth. In 2005-2006, a cohort of 9- and 15-yr-olds (N = 2818) was randomly selected from all regions of Norway. The participation rate was 89% and 74% among the 9-and 15-yr-olds, respectively. We assessed muscular strength by measuring explosive, isometric, and endurance strength. Cardiorespiratory fitness was measured directly as peak oxygen uptake during a cycle ergometry test. Risk factors included in the composite risk factor score (sum of z-scores) were systolic blood pressure, triglyceride, high-density lipoprotein cholesterol, insulin resistance, and waist circumference. Muscle fitness was negatively associated with clustered metabolic risk, independent of cardiorespiratory fitness, and after adjustment for age, sex, and pubertal stage (beta = -0.112, P confidence interval (CI)=4.3-12.0) and 17.3 (95% CI = 9.2-32.7) for muscle fitness and cardiorespiratory fitness, respectively. Our results show that muscle fitness and cardiorespiratory fitness are independently associated with metabolic risk in youth.

  18. Endurance training enhances skeletal muscle interleukin-15 in human male subjects

    DEFF Research Database (Denmark)

    Rinnov, Anders; Yfanti, Christina; Nielsen, Søren

    2014-01-01

    endurance running. With the present study we aimed to determine if muscular IL-15 production would increase in human male subjects following 12 weeks of endurance training. In two different studies we obtained plasma and muscle biopsies from young healthy subjects performing: (1) 12 weeks of ergometer...... weeks of regular endurance training induced a 40% increase in basal skeletal muscle IL-15 protein content (p......Regular endurance exercise promotes metabolic and oxidative changes in skeletal muscle. Overexpression of interleukin-15 (IL-15) in mice exerts similar metabolic changes in muscle as seen with endurance exercise. Muscular IL-15 production has been shown to increase in mice after weeks of regular...

  19. The roles of vitamin D in skeletal muscle: form, function, and metabolism.

    Science.gov (United States)

    Girgis, Christian M; Clifton-Bligh, Roderick J; Hamrick, Mark W; Holick, Michael F; Gunton, Jenny E

    2013-02-01

    Beyond its established role in bone and mineral homeostasis, there is emerging evidence that vitamin D exerts a range of effects in skeletal muscle. Reports of profound muscle weakness and changes in the muscle morphology of adults with vitamin D deficiency have long been described. These reports have been supplemented by numerous trials assessing the impact of vitamin D on muscle strength and mass and falls in predominantly elderly and deficient populations. At a basic level, animal models have confirmed that vitamin D deficiency and congenital aberrations in the vitamin D endocrine system may result in muscle weakness. To explain these effects, some molecular mechanisms by which vitamin D impacts on muscle cell differentiation, intracellular calcium handling, and genomic activity have been elucidated. There are also suggestions that vitamin D alters muscle metabolism, specifically its sensitivity to insulin, which is a pertinent feature in the pathophysiology of insulin resistance and type 2 diabetes. We will review the range of human clinical, animal, and cell studies that address the impact of vitamin D in skeletal muscle, and discuss the controversial issues. This is a vibrant field of research and one that continues to extend the frontiers of knowledge of vitamin D's broad functional repertoire.

  20. Predominant alpha2/beta2/gamma3 AMPK activation during exercise in human skeletal muscle

    DEFF Research Database (Denmark)

    Birk, Jesper Bratz; Wojtaszewski, Jørgen

    2006-01-01

    5'AMP-activated protein kinase (AMPK) is a key regulator of cellular metabolism and is regulated in muscle during exercise. We have previously established that only three of 12 possible AMPK a/ß/¿-heterotrimers are present in human skeletal muscle. Previous studies describe discrepancies between ...

  1. GLUT-3 expression in human skeletal muscle

    Science.gov (United States)

    Stuart, C. A.; Wen, G.; Peng, B. H.; Popov, V. L.; Hudnall, S. D.; Campbell, G. A.

    2000-01-01

    Muscle biopsy homogenates contain GLUT-3 mRNA and protein. Before these studies, it was unclear where GLUT-3 was located in muscle tissue. In situ hybridization using a midmolecule probe demonstrated GLUT-3 within all muscle fibers. Fluorescent-tagged antibody reacting with affinity-purified antibody directed at the carboxy-terminus demonstrated GLUT-3 protein in all fibers. Slow-twitch muscle fibers, identified by NADH-tetrazolium reductase staining, possessed more GLUT-3 protein than fast-twitch fibers. Electron microscopy using affinity-purified primary antibody and gold particle-tagged second antibody showed that the majority of GLUT-3 was in association with triads and transverse tubules inside the fiber. Strong GLUT-3 signals were seen in association with the few nerves that traversed muscle sections. Electron microscopic evaluation of human peripheral nerve demonstrated GLUT-3 within the axon, with many of the particles related to mitochondria. GLUT-3 protein was found in myelin but not in Schwann cells. GLUT-1 protein was not present in nerve cells, axons, myelin, or Schwann cells but was seen at the surface of the peripheral nerve in the perineurium. These studies demonstrated that GLUT-3 mRNA and protein are expressed throughout normal human skeletal muscle, but the protein is predominantly found in the triads of slow-twitch muscle fibers.

  2. Human Leg Model Predicts Muscle Forces, States, and Energetics during Walking.

    Directory of Open Access Journals (Sweden)

    Jared Markowitz

    2016-05-01

    Full Text Available Humans employ a high degree of redundancy in joint actuation, with different combinations of muscle and tendon action providing the same net joint torque. Both the resolution of these redundancies and the energetics of such systems depend on the dynamic properties of muscles and tendons, particularly their force-length relations. Current walking models that use stock parameters when simulating muscle-tendon dynamics tend to significantly overestimate metabolic consumption, perhaps because they do not adequately consider the role of elasticity. As an alternative, we posit that the muscle-tendon morphology of the human leg has evolved to maximize the metabolic efficiency of walking at self-selected speed. We use a data-driven approach to evaluate this hypothesis, utilizing kinematic, kinetic, electromyographic (EMG, and metabolic data taken from five participants walking at self-selected speed. The kinematic and kinetic data are used to estimate muscle-tendon lengths, muscle moment arms, and joint moments while the EMG data are used to estimate muscle activations. For each subject we perform an optimization using prescribed skeletal kinematics, varying the parameters that govern the force-length curve of each tendon as well as the strength and optimal fiber length of each muscle while seeking to simultaneously minimize metabolic cost and maximize agreement with the estimated joint moments. We find that the metabolic cost of transport (MCOT values of our participants may be correctly matched (on average 0.36±0.02 predicted, 0.35±0.02 measured with acceptable joint torque fidelity through application of a single constraint to the muscle metabolic budget. The associated optimal muscle-tendon parameter sets allow us to estimate the forces and states of individual muscles, resolving redundancies in joint actuation and lending insight into the potential roles and control objectives of the muscles of the leg throughout the gait cycle.

  3. Human Leg Model Predicts Muscle Forces, States, and Energetics during Walking.

    Science.gov (United States)

    Markowitz, Jared; Herr, Hugh

    2016-05-01

    Humans employ a high degree of redundancy in joint actuation, with different combinations of muscle and tendon action providing the same net joint torque. Both the resolution of these redundancies and the energetics of such systems depend on the dynamic properties of muscles and tendons, particularly their force-length relations. Current walking models that use stock parameters when simulating muscle-tendon dynamics tend to significantly overestimate metabolic consumption, perhaps because they do not adequately consider the role of elasticity. As an alternative, we posit that the muscle-tendon morphology of the human leg has evolved to maximize the metabolic efficiency of walking at self-selected speed. We use a data-driven approach to evaluate this hypothesis, utilizing kinematic, kinetic, electromyographic (EMG), and metabolic data taken from five participants walking at self-selected speed. The kinematic and kinetic data are used to estimate muscle-tendon lengths, muscle moment arms, and joint moments while the EMG data are used to estimate muscle activations. For each subject we perform an optimization using prescribed skeletal kinematics, varying the parameters that govern the force-length curve of each tendon as well as the strength and optimal fiber length of each muscle while seeking to simultaneously minimize metabolic cost and maximize agreement with the estimated joint moments. We find that the metabolic cost of transport (MCOT) values of our participants may be correctly matched (on average 0.36±0.02 predicted, 0.35±0.02 measured) with acceptable joint torque fidelity through application of a single constraint to the muscle metabolic budget. The associated optimal muscle-tendon parameter sets allow us to estimate the forces and states of individual muscles, resolving redundancies in joint actuation and lending insight into the potential roles and control objectives of the muscles of the leg throughout the gait cycle.

  4. Multi-frequency bioimpedance in human muscle assessment

    DEFF Research Database (Denmark)

    Bartels, Else Marie; Sørensen, Emma Rudbæk; Harrison, Adrian Paul

    2015-01-01

    Bioimpedance analysis (BIA) is a well-known and tested method for body mass and muscular health assessment. Multi-frequency BIA (mfBIA) equipment now makes it possible to assess a particular muscle as a whole, as well as looking at a muscle at the fiber level. The aim of this study was to test...... the hypothesis that mfBIA can be used to assess the anatomical, physiological, and metabolic state of skeletal muscles. mfBIA measurements focusing on impedance, resistance, reactance, phase angle, center frequency, membrane capacitance, and both extracellular and intracellular resistance were carried out. Eight...... healthy human control subjects and three selected cases were examined to demonstrate the extent to which this method may be used clinically, and in relation to training in sport. The electrode setup is shown to affect the mfBIA parameters recorded. Our recommendation is the use of noble metal electrodes...

  5. Low muscle fitness is associated with metabolic risk in youth

    DEFF Research Database (Denmark)

    Steene-Johannessen, Jostein; Anderssen, Sigmund A; Kolle, Elin

    2009-01-01

    PURPOSE: To examine the independent associations of muscle fitness and cardiorespiratory fitness with clustered metabolic risk in youth. METHODS: In 2005-2006, a cohort of 9- and 15-yr-olds (N = 2818) was randomly selected from all regions of Norway. The participation rate was 89% and 74% among...... the 9-and 15-yr-olds, respectively. We assessed muscular strength by measuring explosive, isometric, and endurance strength. Cardiorespiratory fitness was measured directly as peak oxygen uptake during a cycle ergometry test. Risk factors included in the composite risk factor score (sum of z......-scores) were systolic blood pressure, triglyceride, high-density lipoprotein cholesterol, insulin resistance, and waist circumference. RESULTS: Muscle fitness was negatively associated with clustered metabolic risk, independent of cardiorespiratory fitness, and after adjustment for age, sex, and pubertal stage...

  6. Aerobic vs anaerobic metabolism during ischemia in heart muscle.

    Science.gov (United States)

    Das, D K; Engelman, R M; Rousou, J A; Breyer, R H

    1987-01-01

    Anaerobic metabolism in heart muscle plays a role in maintenance of myocardial preservation only during ischemia or hypoxia. In an ischemic state, such as during a heart attack or even during the induced ischemia of open heart surgery, there is impairment of blood flow to the myocardium. The major energy-yielding process in the heart is through the metabolism of glucose and lipids by oxidative reactions. Under anaerobic conditions, oxygen is not available to accept the electrons in the metabolic degradation of substrates and anaerobic glycolysis becomes important in the preservation of myocardial viability during the ischemic process. Unfortunately, the accumulated products of glycolysis, namely protons and lactate, work to inhibit glycolysis, ultimately resulting in a depression of anaerobic metabolism. Cardioplegia, as utilized during open heart surgery, has the effect of inducing instantaneous induction of myocardial mechanical and electrical arrest with a maximal inhibition of the energy utilizing metabolic processes. This effectively reduces substrate utilization and prevents the deleterious consequences of the ischemic process. Cardioplegia is most effective when combined with the additive properties of hypothermia, which plays a significant role in decreasing myocardial metabolism. However, during prolonged hypothermic cardioplegic arrest, sufficient ATP cannot be maintained for cellular integrity and anaerobic glycolysis becomes of increasing importance for maintenance of myocardial preservation. This presentation deals with the mechanics of aerobic versus anaerobic metabolism during the ischemic process of open heart surgery.

  7. Muscle Lipid Metabolism: Role of Lipid Droplets and Perilipins

    Directory of Open Access Journals (Sweden)

    Pablo Esteban Morales

    2017-01-01

    Full Text Available Skeletal muscle is one of the main regulators of carbohydrate and lipid metabolism in our organism, and therefore, it is highly susceptible to changes in glucose and fatty acid (FA availability. Skeletal muscle is an extremely complex tissue: its metabolic capacity depends on the type of fibers it is made up of and the level of stimulation it undergoes, such as acute or chronic contraction. Obesity is often associated with increased FA levels, which leads to the accumulation of toxic lipid intermediates, oxidative stress, and autophagy in skeletal fibers. This lipotoxicity is one of the most common causes of insulin resistance (IR. In this scenario, the “isolation” of certain lipids in specific cell compartments, through the action of the specific lipid droplet, perilipin (PLIN family of proteins, is conceived as a lifeguard compensatory strategy. In this review, we summarize the cellular mechanism underlying lipid mobilization and metabolism inside skeletal muscle, focusing on the function of lipid droplets, the PLIN family of proteins, and how these entities are modified in exercise, obesity, and IR conditions.

  8. Expression profiling reveals metabolic and structural components of extraocular muscles.

    Science.gov (United States)

    Fischer, M Dominik; Gorospe, J Rafael; Felder, Edward; Bogdanovich, Sasha; Pedrosa-Domellöf, F; Ahima, Rexford S; Rubinstein, Neal A; Hoffman, Eric P; Khurana, Tejvir S

    2002-01-01

    The extraocular muscles (EOM) are anatomically and physiologically distinct from other skeletal muscles. EOM are preferentially affected in mitochondrial myopathies, but spared in Duchenne's muscular dystrophy. The anatomical and pathophysiological properties of EOM have been attributed to their unique molecular makeup: an allotype. We used expression profiling to define molecular features of the EOM allotype. We found 346 differentially expressed genes in rat EOM compared with tibialis anterior, based on a twofold difference cutoff. Genes required for efficient, fatigue-resistant, oxidative metabolism were increased in EOM, whereas genes for glycogen metabolism were decreased. EOM also showed increased expression of genes related to structural components of EOM such as vessels, nerves, mitochondria, and neuromuscular junctions. Additionally, genes related to specialized functional roles of EOM such as the embryonic and EOM-specific myosin heavy chains and genes for muscle growth, development, and/or regeneration were increased. The EOM expression profile was validated using biochemical, structural, and molecular methods. Characterization of the EOM expression profile begins to define gene transcription patterns associated with the unique anatomical, metabolic, and pathophysiological properties of EOM.

  9. Growth hormone enhances effects of endurance training on oxidative muscle metabolism in elderly women

    DEFF Research Database (Denmark)

    Lange, K H; Isaksson, F; Juul, A

    2000-01-01

    The present study investigated whether recombinant human (rh) growth hormone (GH) combined with endurance training would have a larger effect on oxidative capacity, metabolism, and body fat than endurance training alone. Sixteen healthy, elderly women, aged 75 yr, performed closely monitored...... in the two subjects receiving rhGH. In conclusion, rhGH adds to the effects of endurance training on muscle oxidative enzymes and causes a reduction in body fat in elderly women....

  10. Human muscle net K(+) release during exercise is unaffected by elevated anaerobic metabolism, but reduced after prolonged acclimatization to 4,100 m.

    Science.gov (United States)

    Nordsborg, Nikolai B; Calbet, José A L; Sander, Mikael; van Hall, Gerrit; Juel, Carsten; Saltin, Bengt; Lundby, Carsten

    2010-07-01

    It was investigated whether skeletal muscle K(+) release is linked to the degree of anaerobic energy production. Six subjects performed an incremental bicycle exercise test in normoxic and hypoxic conditions prior to and after 2 and 8 wk of acclimatization to 4,100 m. The highest workload completed by all subjects in all trials was 260 W. With acute hypoxic exposure prior to acclimatization, venous plasma [K(+)] was lower (P exercise intensity, leg net K(+) release was unaffected by hypoxic exposure independent of acclimatization. After 8 wk of acclimatization, no difference existed in venous plasma [K(+)] between the normoxic and hypoxic trial, either at submaximal intensities or at exhaustion (360 +/- 14 W vs. 313 +/- 8 W; P exercise intensity, leg net K(+) release was less (P exercise relative to rest was less (P anaerobic energy production and that acclimatization reduces leg net K(+) release during exercise.

  11. Human muscle net K+ release during exercise is unaffected by elevated anaerobic metabolism, but reduced after prolonged acclimatization to 4100 m

    DEFF Research Database (Denmark)

    Nordsborg, Nikolai Baastrup; Calbet, Jose A. L.; Sander, Mikael

    2010-01-01

    It was investigated if skeletal muscle K(+) release is linked to the degree of anaerobic energy production. Six subjects performed an incremental bicycle exercise test in normoxic and hypoxic conditions prior to and after 2 and 8 weeks of acclimatization to 4100 m. The highest workload completed...... absolute exercise intensity, leg net K(+) release was unaffected by hypoxic exposure independent of acclimatization. After 8 weeks of acclimatization no difference existed in venous plasma [K(+)] between the normoxic and hypoxic trial, neither at submaximal intensities nor at exhaustion (360+/-14 W vs. 313...... (Pdegree of acclimatization (at 260 W prior to acclimatization: -10.0+/-0.4 % in normoxia and -4.9+/-0.8 % in hypoxia). It is concluded that leg net K(+) release is unrelated to anaerobic energy production and that acclimatization...

  12. Female hormones: do they influence muscle and tendon protein metabolism?

    DEFF Research Database (Denmark)

    Hansen, Mette

    2018-01-01

    (or lack of female hormones) on skeletal muscle protein turnover at rest and in response to exercise. This review is primarily based on data from human trials. Many elderly post-menopausal women experience physical disabilities and loss of independence related to sarcopenia, which reduces life quality...... and is associated with substantial financial costs. Resistance training and dietary optimisation can counteract or at least decelerate the degenerative ageing process, but lack of oestrogen in post-menopausal women may reduce their sensitivity to these anabolic stimuli and accelerate muscle loss. Tendons...... oestrogen seems to play a significant role with regard to skeletal muscle protein turnover. Therefore, oestrogen/hormonal replacement therapy may counteract the degenerative changes in skeletal muscle. Nevertheless, there is a need for greater insight into the direct and indirect mechanistic effects...

  13. Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men.

    Science.gov (United States)

    Blondin, Denis P; Labbé, Sébastien M; Phoenix, Serge; Guérin, Brigitte; Turcotte, Éric E; Richard, Denis; Carpentier, André C; Haman, François

    2015-02-01

    Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized. Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-(13)C]-palmitate and [3-(3)H]-glucose tracer methodologies coupled with positron emission tomography using (11)C-acetate and (18)F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of

  14. Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females

    DEFF Research Database (Denmark)

    Ribas, Vicent; Drew, Brian G; Zhou, Zhenqi

    2016-01-01

    Impaired estrogen receptor α (ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established...... that reduced ERα expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERα knockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism...... and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A-regulator of calcineurin 1-calcineurin signaling through dynamin...

  15. Influence of pre-exercise muscle glycogen content on exercise-induced transcriptional regulation of metabolic genes

    DEFF Research Database (Denmark)

    Pilegaard, Henriette; Keller, Charlotte; Steensberg, Adam

    2002-01-01

    Transcription of metabolic genes is transiently induced during recovery from exercise in skeletal muscle of humans. To determine whether pre-exercise muscle glycogen content influences the magnitude and/or duration of this adaptive response, six male subjects performed one-legged cycling exercise...... and UCP3 mRNA in response to exercise was also significantly higher in the low glycogen (11.4- and 3.5-fold, respectively) than in the control (5.0- and 1.7-fold, respectively) trial. These data indicate that low muscle glycogen content enhances the transcriptional activation of some metabolic genes...... to lower muscle glycogen content in one leg and then, the following day, completed 2.5 h low intensity two-legged cycling exercise. Nuclei and mRNA were isolated from biopsies obtained from the vastus lateralis muscle of the control and reduced glycogen (pre-exercise glycogen = 609 +/- 47 and 337 +/- 33...

  16. Effect of metformin on glucose metabolism in mouse soleus muscle.

    Science.gov (United States)

    Bailey, C J; Puah, J A

    1986-08-01

    To investigate the antihyperglycaemic effect of metformin (dimethylbiguanide), insulin binding and glucose metabolism were examined in soleus muscles isolated from streptozotocin diabetic mice. Treatment with metformin (250 mg/kg/day orally for 3 weeks) reduced by 39% the severity of streptozotocin-induced hyperglycaemia. Soleus muscles of metformin treated mice showed a 41% increase in total insulin receptor number, and a 20% increase in 3-0-methylglucose uptake at both submaximally and maximally stimulating insulin concentrations. Oxidation of U-14C-glucose to 14CO2 and the formation of 14C-glycogen were increased by 25% and 30% respectively at maximally stimulating insulin concentrations, but not at submaximally stimulating concentrations. Lactate formation was not significantly altered. Maximum activity of hexokinase (EC 2.7.1.1) was increased by 35%, and this effect was independent of insulin. The results suggest that the antihyperglycaemic effect of metformin in streptozotocin diabetic mice is related in part to an increase in insulin-mediated glucose uptake and oxidative metabolism in skeletal muscle.

  17. The Emerging Role of Skeletal Muscle Metabolism as a Biological Target and Cellular Regulator of Cancer-Induced Muscle Wasting

    Science.gov (United States)

    Carson, James A.; Hardee, Justin P.; VanderVeen, Brandon N.

    2015-01-01

    While skeletal muscle mass is an established primary outcome related to understanding cancer cachexia mechanisms, considerable gaps exist in our understanding of muscle biochemical and functional properties that have recognized roles in systemic health. Skeletal muscle quality is a classification beyond mass, and is aligned with muscle’s metabolic capacity and substrate utilization flexibility. This supplies an additional role for the mitochondria in cancer-induced muscle wasting. While the historical assessment of mitochondria content and function during cancer-induced muscle loss was closely aligned with energy flux and wasting susceptibility, this understanding has expanded to link mitochondria dysfunction to cellular processes regulating myofiber wasting. The primary objective of this article is to highlight muscle mitochondria and oxidative metabolism as a biological target of cancer cachexia and also as a cellular regulator of cancer-induced muscle wasting. Initially, we examine the role of muscle metabolic phenotype and mitochondria content in cancer-induced wasting susceptibility. We then assess the evidence for cancer-induced regulation of skeletal muscle mitochondrial biogenesis, dynamics, mitophagy, and oxidative stress. In addition, we discuss environments associated with cancer cachexia that can impact the regulation of skeletal muscle oxidative metabolism. The article also examines the role of cytokine-mediated regulation of mitochondria function regulation, followed by the potential role of cancer-induced hypogonadism. Lastly, a role for decreased muscle use in cancer-induced mitochondrial dysfunction is reviewed. PMID:26593326

  18. The Emerging Role of Skeletal Muscle Metabolism as a Biological Target and Cellular Regulator of Cancer-Induced Muscle Wasting

    OpenAIRE

    Carson, James A.; Hardee, Justin P.; VanderVeen, Brandon N.

    2015-01-01

    While skeletal muscle mass is an established primary outcome related to understanding cancer cachexia mechanisms, considerable gaps exist in our understanding of muscle biochemical and functional properties that have recognized roles in systemic health. Skeletal muscle quality is a classification beyond mass, and is aligned with muscle���s metabolic capacity and substrate utilization flexibility. This supplies an additional role for the mitochondria in cancer-induced muscle wasting. While the...

  19. Defective Homocysteine Metabolism: Potential Implications for Skeletal Muscle Malfunction

    Directory of Open Access Journals (Sweden)

    Suresh C. Tyagi

    2013-07-01

    Full Text Available Hyperhomocysteinemia (HHcy is a systemic medical condition and has been attributed to multi-organ pathologies. Genetic, nutritional, hormonal, age and gender differences are involved in abnormal homocysteine (Hcy metabolism that produces HHcy. Homocysteine is an intermediate for many key processes such as cellular methylation and cellular antioxidant potential and imbalances in Hcy production and/or catabolism impacts gene expression and cell signaling including GPCR signaling. Furthermore, HHcy might damage the vagus nerve and superior cervical ganglion and affects various GPCR functions; therefore it can impair both the parasympathetic and sympathetic regulation in the blood vessels of skeletal muscle and affect long-term muscle function. Understanding cellular targets of Hcy during HHcy in different contexts and its role either as a primary risk factor or as an aggravator of certain disease conditions would provide better interventions. In this review we have provided recent Hcy mediated mechanistic insights into different diseases and presented potential implications in the context of reduced muscle function and integrity. Overall, the impact of HHcy in various skeletal muscle malfunctions is underappreciated; future studies in this area will provide deeper insights and improve our understanding of the association between HHcy and diminished physical function.

  20. Liver, but not muscle, has an entrainable metabolic memory.

    Directory of Open Access Journals (Sweden)

    Sheng-Song Chen

    Full Text Available Hyperglycemia in the hospitalized setting is common, especially in patients that receive nutritional support either continuously or intermittently. As the liver and muscle are the major sites of glucose disposal, we hypothesized their metabolic adaptations are sensitive to the pattern of nutrient delivery. Chronically catheterized, well-controlled depancreatized dogs were placed on one of three isocaloric diets: regular chow diet once daily (Chow or a simple nutrient diet (ND that was given either once daily (ND-4 or infused continuously (ND-C. Intraportal insulin was infused to maintain euglycemia. After 5 days net hepatic (NHGU and muscle (MGU glucose uptake and oxidation were assessed at euglycemia (120 mg/dl and hyperglycemia (200 mg/dl in the presence of basal insulin. While hyperglycemia increased both NHGU and MGU in Chow, NHGU was amplified in both groups receiving ND. The increase was associated with enhanced activation of glycogen synthase, glucose oxidation and suppression of pyruvate dehydrogenase kinase-4 (PDK-4. Accelerated glucose-dependent muscle glucose uptake was only evident with ND-C. This was associated with a decrease in PDK-4 expression and an increase in AMP-activated protein kinase (AMPK phosphorylation. Interestingly, ND-C markedly increased hepatic FGF-21 expression. Thus, augmentation of carbohydrate disposal in the liver, as opposed to the muscle, is not dependent on the pattern of nutrient delivery.

  1. Disorders of muscle lipid metabolism: diagnostic and therapeutic challenges.

    Science.gov (United States)

    Laforêt, Pascal; Vianey-Saban, Christine

    2010-11-01

    Disorders of muscle lipid metabolism may involve intramyocellular triglyceride degradation, carnitine uptake, long-chain fatty acids mitochondrial transport, or fatty acid β-oxidation. Three main diseases leading to permanent muscle weakness are associated with severe increased muscle lipid content (lipid storage myopathies): primary carnitine deficiency, neutral lipid storage disease and multiple acyl-CoA dehydrogenase deficiency. A moderate lipidosis may be observed in fatty acid oxidation disorders revealed by rhabdomyolysis episodes such as carnitine palmitoyl transferase II, very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein deficiencies, and in recently described phosphatidic acid phosphatase deficiency. Respiratory chain disorders and congenital myasthenic syndromes may also be misdiagnosed as fatty acid oxidation disorders due to the presence of secondary muscle lipidosis. The main biochemical tests giving clues for the diagnosis of these various disorders are measurements of blood carnitine and acylcarnitines, urinary organic acid profile, and search for intracytoplasmic lipid on peripheral blood smear (Jordan's anomaly). Genetic analysis orientated by the results of biochemical investigation allows establishing a firm diagnosis. Primary carnitine deficiency and multiple acyl-CoA dehydrogenase deficiency may be treated after supplementation with carnitine, riboflavine and coenzyme Q10. New therapeutic approaches for fatty acid oxidation disorders are currently developed, based on pharmacological treatment with bezafibrate, and specific diets enriched in medium-chain triglycerides or triheptanoin. Copyright © 2010 Elsevier B.V. All rights reserved.

  2. Metabolism of perfused pig intercostal muscles evaluated by 31P-magnetic resonance spectroscopy

    DEFF Research Database (Denmark)

    Pedersen, Brian Lindegaard; Arendrup, Henrik; Secher, Niels H

    2006-01-01

    This study presents a perfused preparation for evaluation of metabolism in pig intercostal muscle in vitro. Preserved vessels and nerves to an intercostal segment including two adjacent ribs allowed for tissue perfusion and electrical stimulation with measurement of contraction force, oxygen...... and 3.5 +/- 0.5 micromol min(-1) g(-1) during the two last minutes, corresponding to the drop in force. When the preparation was left unperfused, anaerobic ATP turnover averaged 0.40 +/- 0.15 micromol min(-1) g(-1) for the first 10 min. The preparation can also be applied to human intercostal muscles......, as demonstrated in one preliminary experiment. The results demonstrate a stable and functional in vitro preparation of intact perfused intercostal muscles in the pig....

  3. Skeletal muscle metabolism during prolonged exercise in Pompe disease

    Directory of Open Access Journals (Sweden)

    Nicolai Preisler

    2017-07-01

    Full Text Available Objective: Pompe disease (glycogenosis type II is caused by lysosomal alpha-glucosidase deficiency, which leads to a block in intra-lysosomal glycogen breakdown. In spite of enzyme replacement therapy, Pompe disease continues to be a progressive metabolic myopathy. Considering the health benefits of exercise, it is important in Pompe disease to acquire more information about muscle substrate use during exercise. Methods: Seven adults with Pompe disease were matched to a healthy control group (1:1. We determined (1 peak oxidative capacity (VO2peak and (2 carbohydrate and fatty acid metabolism during submaximal exercise (33 W for 1 h, using cycle-ergometer exercise, indirect calorimetry and stable isotopes. Results: In the patients, VO2peak was less than half of average control values; mean difference −1659 mL/min (CI: −2450 to −867, P = 0.001. However, the respiratory exchange ratio increased to >1.0 and lactate levels rose 5-fold in the patients, indicating significant glycolytic flux. In line with this, during submaximal exercise, the rates of oxidation (ROX of carbohydrates and palmitate were similar between patients and controls (mean difference 0.226 g/min (CI: 0.611 to −0.078, P = 0.318 and mean difference 0.016 μmol/kg/min (CI: 1.287 to −1.255, P = 0.710, respectively. Conclusion: Reflecting muscle weakness and wasting, Pompe disease is associated with markedly reduced maximal exercise capacity. However, glycogenolysis is not impaired in exercise. Unlike in other metabolic myopathies, skeletal muscle substrate use during exercise is normal in Pompe disease rendering exercise less complicated for e.g. medical or recreational purposes.

  4. Skeletal muscle metabolism during prolonged exercise in Pompe disease.

    Science.gov (United States)

    Preisler, Nicolai; Laforêt, Pascal; Madsen, Karen Lindhardt; Husu, Edith; Vissing, Christoffer Rasmus; Hedermann, Gitte; Galbo, Henrik; Lindberg, Christopher; Vissing, John

    2017-08-01

    Pompe disease (glycogenosis type II) is caused by lysosomal alpha-glucosidase deficiency, which leads to a block in intra-lysosomal glycogen breakdown. In spite of enzyme replacement therapy, Pompe disease continues to be a progressive metabolic myopathy. Considering the health benefits of exercise, it is important in Pompe disease to acquire more information about muscle substrate use during exercise. Seven adults with Pompe disease were matched to a healthy control group (1:1). We determined (1) peak oxidative capacity (VO2peak) and (2) carbohydrate and fatty acid metabolism during submaximal exercise (33 W) for 1 h, using cycle-ergometer exercise, indirect calorimetry and stable isotopes. In the patients, VO2peak was less than half of average control values; mean difference -1659 mL/min (CI: -2450 to -867, P = 0.001). However, the respiratory exchange ratio increased to >1.0 and lactate levels rose 5-fold in the patients, indicating significant glycolytic flux. In line with this, during submaximal exercise, the rates of oxidation (ROX) of carbohydrates and palmitate were similar between patients and controls (mean difference 0.226 g/min (CI: 0.611 to -0.078, P = 0.318) and mean difference 0.016 µmol/kg/min (CI: 1.287 to -1.255, P = 0.710), respectively). Reflecting muscle weakness and wasting, Pompe disease is associated with markedly reduced maximal exercise capacity. However, glycogenolysis is not impaired in exercise. Unlike in other metabolic myopathies, skeletal muscle substrate use during exercise is normal in Pompe disease rendering exercise less complicated for e.g. medical or recreational purposes. © 2017 The authors.

  5. Postural sway under muscle vibration and muscle fatigue in humans.

    Science.gov (United States)

    Vuillerme, Nicolas; Danion, Frédéric; Forestier, Nicolas; Nougier, Vincent

    2002-11-22

    Separate studies have demonstrated that vibration and fatigue of ankle muscles alter postural control. The purpose of the present experiment was to investigate the effect of ankle muscle vibration on the regulation of postural sway in bipedal stance following ankle muscle fatigue. Center of foot pressure displacements were recorded using a force platform. Results showed a similar increase in postural sway under muscle fatigue as well as under muscle vibration. Interestingly, under muscle fatigue muscle vibration did not induce a further increase in postural sway. Two hypotheses could, at least, account for this observation: (1). fatigued muscles are less sensitive to muscle vibration and (2). the central nervous system relies less upon proprioceptive information originating from fatigued muscles for regulating postural sway.

  6. Human skeletal muscle disuse atrophy: effects on muscle protein synthesis, breakdown and insulin resistance- a qualitative review

    Directory of Open Access Journals (Sweden)

    Supreeth S Rudrappa

    2016-08-01

    Full Text Available The ever increasing burden of an ageing population and pandemic of metabolic syndrome worldwide demands further understanding of the modifiable risk factors in reducing disability and morbidity associated with these conditions. Disuse skeletal muscle atrophy (sometimes referred to as simple atrophy and insulin resistance are ‘non-pathological’ events resulting from sedentary behaviour and periods of enforced immobilization e.g. due to fractures or elective orthopaedic surgery. Yet, the processes and drivers regulating disuse atrophy and insulin resistance and the associated molecular events remain unclear – especially in humans. The aim of this review is to present current knowledge of relationships between muscle protein turnover, insulin resistance and muscle atrophy during disuse, principally in humans. Immobilisation lowers fasted state muscle protein synthesis (MPS and induces fed-state ‘anabolic resistance’. While a lack of dynamic measurements of muscle protein breakdown (MPB precludes defining a definitive role for MPB in disuse atrophy, some proteolytic marker studies (e.g. MPB genes suggest a potential early elevation. Immobilisation also induces muscle insulin resistance (IR. Moreover, the trajectory of muscle atrophy appears to be accelerated in persistent IR states (e.g. Type II diabetes, suggesting IR may contribute to muscle disuse atrophy under these conditions. Nonetheless, the role of differences in insulin sensitivity across distinct muscle groups and its effects on rates of atrophy remains unclear. Multifaceted time-course studies into the collective role of insulin resistance and muscle protein turnover in the setting of disuse muscle atrophy, in humans, are needed to facilitate the development of appropriate countermeasures and efficacious rehabilitation protocols.

  7. THE EFFECT OF RESISTANCE AND ENDURANCE EXERCISE TRAINING ON MUSCLE PROTEOME EXPRESSION IN HUMAN SKELETAL MUSCLE

    Directory of Open Access Journals (Sweden)

    Chang Keun Kim

    2012-04-01

    Full Text Available To investigate the effect of resistance and endurance training on muscle proteome expression, samples of vastus lateralis from 10 physically active young men were analysed by 2-dimensional electrophoresis (2-DE and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS. Differential patterns of protein expression were determined after 4 weeks of endurance or resistance exercise training. Following endurance exercise training, carbonic anhydrase III immunoglobulin heavy chain, myosin heavy chain 1, titin, chromosome 12, and fructose-1,6-bisphosphatase 2 were up-regulated while pyruvate kinase 3 isoform, ubiquitin carboxyl-terminal hydrolase, and phosphoglucomutase were down-regulated. After the 4 weeks of resistance exercise training, five proteins, apolipoprotein A-IV precursor, microtubule-actin cross linking factor 1, myosin light chain, growth hormone inducible transmembrane protein, and an unknown protein were up-regulated and pyruvate kinase 3 isoform, human albumin, and enolase 3 were down-regulated. We conclude that endurance and resistance exercise training differently alter the expression of individual muscle proteins, and that the response of muscle protein expression may be associated with specific myofibre adaptations to exercise training. Proteomic studies represent one of the developing techniques of metabolism which may substantially contribute to new insights into muscle and exercise physiology.

  8. Nitric oxide synthase in human skeletal muscles related to defined fibre types.

    Science.gov (United States)

    Punkt, Karla; Fritzsche, Matthias; Stockmar, Christoph; Hepp, Pierre; Josten, Christoph; Wellner, Maren; Schering, Stefan; Buchwalow, Igor B

    2006-05-01

    Skeletal muscle functions regulated by NO are now firmly established. However, the knowledge about the NO synthase (NOS) expression related to a defined fibre type in human skeletal muscles necessitates further clarification. To address this issue, we examined localization of NOS isoforms I, II and III, in human skeletal muscles employing immunocytochemical labeling with tyramide signal amplification complemented with enzyme histochemistry and Western blotting. The NOS immunoreactivity was related to fibre types of different classification systems: physiological classification into slow and fast, ATPase classification into I, IIA, IIAX, IIX, and physiological-metabolic classification into slow-oxidative (SO), fast-oxidative glycolytic (FOG) and fast-glycolytic (FG). We found a correlation of NOS I-III immunoreactivity to metabolic defined fibre types with strong expression in FOG fibres. This implies that NO as modulator of muscle function is involved in oxidative metabolism in connection with fast force development, which only occurs in FOG fibres. The NOS expression showed no correlation to ATPase fibre subtypes due to the metabolic heterogeneity of ATPase fibre types. Healthy and affected vastus medialis muscles after anterior cruciate ligament rupture revealed similar NOS expression level as shown by Western blotting with, however, different expression patterns related to the fibre types in affected muscles. This suggests an altered modulation of force development in the fibres of diseased muscles.

  9. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    ... metabolism and its impact on patient welfare. After underlining the relationship between efficacy, toxicity and drug concentration, the book then considers how metabolizing systems operate and how they impact upon drug concentration...

  10. Inverse associations between muscle mass, strength, and the metabolic syndrome.

    Science.gov (United States)

    Atlantis, Evan; Martin, Sean A; Haren, Matthew T; Taylor, Anne W; Wittert, Gary A

    2009-07-01

    The metabolic syndrome (MetS) is a clustering of individual cardiovascular disease risk factors, which doubles the risk of early mortality. The authors' aimed to determine the prevalence and population attributable risk (PAR%) of the MetS among men according to demographic, physical, and lifestyle risk factors. A cross-sectional study was conducted in 1195 men in the Florey Adelaide Male Ageing Study, a regionally representative cohort of Australian men aged 35 to 81 years conducted in 2002-2005 (response rate, 45.1%). Prevalent MetS was determined according to the Adult Treatment Panel III (ATPIII) and International Diabetes Federation (IDF) classifications; and an extensive list of demographic, physical (including muscle strength, body composition by dual-energy x-ray absorptiometry, sex hormones), and lifestyle factors was accounted for. Prevalence estimates were 37.7% and 41.8% for ATPIII and IDF classifications. Odds ratios for present MetS were determined using multiple-adjusted logistic regression. Odds for present ATPIII MetS decreased (in order of importance) for lower insulin and increased for lower muscle mass, lower strength, and 3+ medical conditions. Odds for present IDF MetS decreased for lower insulin and increased for lower muscle mass, strength, and sex hormone-binding globulin levels; older age; and being married. Significant PAR% due to lowest insulin, muscle mass, and strength quarters were -44%, 27%, and 17% for the ATPIII Met, and -48%, 31%, and 20% for the IDF MetS. A substantial proportion of MetS cases would have been theoretically prevented if prior exposure to low muscle mass and strength were eradicated (PAR% ranged from 14% to 24%). Findings indicate that insulin resistance is a central abnormality in the MetS and that muscle mass and strength are strong protective factors independent of insulin resistance and abdominal fat accumulation. If confirmed prospectively, increases in muscle mass and strength needed to prevent a substantial

  11. Simultaneous 31P NMR spectroscopy and EMG in exercising and recovering human skeletal muscle: technical aspects

    DEFF Research Database (Denmark)

    Vestergaard-Poulsen, P; Thomsen, C; Sinkjaer, T

    1994-01-01

    The bioenergetics of human skeletal muscle can be studied by 31P NMR spectroscopy (31P-MRS) and by surface electromyography (SEMG). Simultaneous 31P-MRS and SEMG permit accurate and noninvasive studies of the correlation between metabolic and electrical changes in exercising and recovering human ...

  12. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    ..., both under drug pressure and during inhibition. Factors affecting drug metabolism, such as genetic polymorphisms, age and diet are discussed and how metabolism can lead to toxicity is explained. The book concludes with the role of drug metabolism in the commercial development of therapeutic agents as well as the pharmacology of some illicit drugs.

  13. Supplemental oxygen and muscle metabolism in mitochondrial myopathy patients.

    Science.gov (United States)

    Trenell, Michael I; Sue, Carolyn M; Thompson, Campbell H; Kemp, Graham J

    2007-03-01

    Patients with mitochondrial myopathy (MM) have a reduced capacity to perform exercise due to a reduced oxidative capacity. We undertook this study to determine whether skeletal muscle metabolism could be improved with oxygen therapy in patients with MM. Six patients with MM and six controls, matched for age, gender and physical activity, underwent (31)P-magnetic resonance spectroscopy ((31)P-MRS) examination. (31)P-MR spectra were collected at rest and in series during exercise and recovery whilst breathing normoxic (0.21 O(2)) or hyperoxic (1.0 O(2)) air. At rest, MM showed an elevated [ADP] (18 +/- 3 micromol/l) and pH (7.03 +/- 0.01) in comparison to the control group (12 +/- 1 micromol/l, 7.01 +/- 0.01) (P Oxygen supplementation did not change resting metabolites in either MM or the control group (P > 0.05). Inferred maximal ATP synthesis rate improved by 33% with oxygen in MM (21 +/- 3 vs. 28 +/- 5 mmol/(l min), P 0.05). We conclude that oxygen therapy is associated with significant improvements in muscle metabolism in patients with MM. These data suggest that patients with MM could benefit from therapies which improve the provision of oxygen.

  14. Gene polymorphisms and fiber-type composition of human skeletal muscle.

    Science.gov (United States)

    Ahmetov, Ildus I; Vinogradova, Olga L; Williams, Alun G

    2012-08-01

    The ability to perform aerobic or anaerobic exercise varies widely among individuals, partially depending on their muscle-fiber composition. Variability in the proportion of skeletal-muscle fiber types may also explain marked differences in aspects of certain chronic disease states including obesity, insulin resistance, and hypertension. In untrained individuals, the proportion of slow-twitch (Type I) fibers in the vastus lateralis muscle is typically around 50% (range 5-90%), and it is unusual for them to undergo conversion to fast-twitch fibers. It has been suggested that the genetic component for the observed variability in the proportion of Type I fibers in human muscles is on the order of 40-50%, indicating that muscle fiber-type composition is determined by both genotype and environment. This article briefly reviews current progress in the understanding of genetic determinism of fiber-type proportion in human skeletal muscle. Several polymorphisms of genes involved in the calcineurin-NFAT pathway, mitochondrial biogenesis, glucose and lipid metabolism, cytoskeletal function, hypoxia and angiogenesis, and circulatory homeostasis have been associated with fiber-type composition. As muscle is a major contributor to metabolism and physical strength and can readily adapt, it is not surprising that many of these gene variants have been associated with physical performance and athlete status, as well as metabolic and cardiovascular diseases. Genetic variants associated with fiber-type proportions have important implications for our understanding of muscle function in both health and disease.

  15. Muscle metabolism during graded quadriceps exercise in man

    DEFF Research Database (Denmark)

    Helge, Jørn W; Stallknecht, Bente; Galbo, Henrik

    2007-01-01

    veins, and thigh blood flow was determined by thermodilution. Muscle biopsies were obtained from m. vastus lateralis of both thighs. From rest through exercise at 25, 65 and 85% Wmax the thigh blood flow (0.3+/-0.1, 2.5+/-0.2, 3.5+/-0.2, 4.1+/-0.3 l min(-1)) and oxygen uptake (0.02+/-0.01, 0......The aim of the study was to examine local muscle metabolism in response to graded exercise when the involved muscle mass is too small to elicit marked hormonal changes and local blood flow restriction. Nine healthy overnight fasted male subjects performed knee extension exercise with both thighs...... kicking at 25% of maximal power (Wmax) for 45 min (23+/-1% of pulmonary) followed by 35 min of kicking with one thigh at 65% and the other at 85% W(max) (40+/-1% ). Primed constant infusion of [U-13C] palmitate and [2H5]glycerol was carried out. Blood was sampled from a femoral artery and both femoral...

  16. Narciclasine attenuates diet-induced obesity by promoting oxidative metabolism in skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Sofi G Julien

    2017-02-01

    Full Text Available Obesity develops when caloric intake exceeds metabolic needs. Promoting energy expenditure represents an attractive approach in the prevention of this fast-spreading epidemic. Here, we report a novel pharmacological strategy in which a natural compound, narciclasine (ncls, attenuates diet-induced obesity (DIO in mice by promoting energy expenditure. Moreover, ncls promotes fat clearance from peripheral metabolic tissues, improves blood metabolic parameters in DIO mice, and protects these mice from the loss of voluntary physical activity. Further investigation suggested that ncls achieves these beneficial effects by promoting a shift from glycolytic to oxidative muscle fibers in the DIO mice thereby enhancing mitochondrial respiration and fatty acid oxidation (FAO in the skeletal muscle. Moreover, ncls strongly activates AMPK signaling specifically in the skeletal muscle. The beneficial effects of ncls treatment in fat clearance and AMPK activation were faithfully reproduced in vitro in cultured murine and human primary myotubes. Mechanistically, ncls increases cellular cAMP concentration and ADP/ATP ratio, which further lead to the activation of AMPK signaling. Blocking AMPK signaling through a specific inhibitor significantly reduces FAO in myotubes. Finally, ncls also enhances mitochondrial membrane potential and reduces the formation of reactive oxygen species in cultured myotubes.

  17. Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism.

    Science.gov (United States)

    Uruno, Akira; Yagishita, Yoko; Katsuoka, Fumiki; Kitajima, Yasuo; Nunomiya, Aki; Nagatomi, Ryoichi; Pi, Jingbo; Biswal, Shyam S; Yamamoto, Masayuki

    2016-06-01

    Nrf2 (NF-E2-related factor 2) contributes to the maintenance of glucose homeostasis in vivo Nrf2 suppresses blood glucose levels by protecting pancreatic β cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1 knockout (Keap1MuKO) mice that express abundant Nrf2 in their SkM and then examined Nrf2 target gene expression in that tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated and the levels of the glycogen branching enzyme (Gbe1) and muscle-type PhKα subunit (Phka1) mRNAs, along with those of the glycogen branching enzyme (GBE) and the phosphorylase b kinase α subunit (PhKα) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2 inducers promoted Gbe1 and Phka1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 and Phka1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2 induction in SkM increases GBE and PhKα expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Our results also indicate that Nrf2 differentially regulates glycogen metabolism in SkM and the liver. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  18. Human skeletal muscle fibroblasts stimulate in vitro myogenesis and in vivo muscle regeneration

    DEFF Research Database (Denmark)

    Mackey, Abigail L.; Magnan, Mélanie; Chazaud, Bénédicte

    2017-01-01

    Accumulation of skeletal muscle extracellular matrix is an unfavourable characteristic of many muscle diseases, muscle injury and sarcopenia. In addition to the indispensable role satellite cells play in muscle regeneration, there is emerging evidence in rodents for a regulatory influence...... and strongly stimulate both MPC differentiation and MPC fusion. It thus appears, in humans, that fibroblasts exert a strong positive regulatory influence on MPC activity, in line with observations during in vivo skeletal muscle regeneration....

  19. Human metabolism and metabolic interactions of deployment-related chemicals.

    Science.gov (United States)

    Hodgson, Ernest; Rose, Randy L

    2005-01-01

    It has been suggested that chemicals and, more specifically, chemical interactions, are involved as causative agents in deployment-related illnesses. Unfortunately, this hypothesis has proven difficult to test, because toxicological investigations of deployment-related chemicals are usually carried out on surrogate animals and are difficult to extrapolate to humans. Other parts of the problem, such as the definition of variation within human populations and the development of methods for designating groups or individuals at significantly greater risk, cannot be carried out on surrogate animals, and the data must be derived from humans. The relatively recent availability of human cell.fractions, such as microsomes, cytosol, etc., human cells such as primary hepatocytes, recombinant human enzymes, and their isoforms and polymorphic variants has enabled a significant start to be made in developing the human data needed. These initial studies have examined the human metabolism by cytochrome P450, other phase I enzymes, and their isoforms and, in some cases, their polymorphic variants of compounds such as chlorpyrifos, carbaryl, DEET, permethrin, and pyridostigmine bromide, and, to a lesser extent, other chemicals from the same chemical and use classes, including solvents, jet fuel components, and sulfur mustard metabolites. A number of interactions at the metabolic level have been described both with respect to other xenobiotics and to endogenous metabolites. Probably the most dramatic have been seen in the ability of chlorpyrifos to inhibit not only the metabolism of other xenobiotics such as carbaryl and DEET but also to inhibit the metabolism of steroid hormones.

  20. Glucose metabolism in rats submitted to skeletal muscle denervation

    Directory of Open Access Journals (Sweden)

    Wilton Marlindo Santana Nunes

    2005-07-01

    Full Text Available This study analyzed the local and systemic effects of immobilization by denervation of the skeletal muscle on glucose metabolism. The rats were submitted to section of the right paw sciatic nerve. A reduction was observed in glucose uptake by the isolated soleus muscle of the denervated paw after 3 and 7 days, but not after 28 days in relation to the control animals. There was no difference after 3 and 7 days in glucose uptake by the soleus muscle of the opposite intact paw in relation to the control. There was increased glucose uptake in the same paw 28 days after denervation. The rate of glucose removal in response to exogenous insulin after 28 days of denervation was significantly higher than in control animals and those observed after 3 and 7 days of denervation. These results suggest that immobilization by denervation interfered not only in glucose metabolism in the skeletal muscle involved but also in other tissues.O estudo analisou os efeitos locais e sistêmicos da imobilização por desnervação do músculo esquelético sobre o metabolismo glicidico. Ratos foram submetidos à secção do nervo ciático da pata direita. Observou-se redução da captação de glicose pelo músculo sóleo isolado da pata desnervada após 3 e 7 mas não após 28 dias em relação a animais controle. Não houve diferença após 3 e 7 dias na captação de glicose pelo músculo sóleo da pata contralateral intacta em relação ao controle. Houve aumento da captação de glicose nesta mesma pata 28 dias após a desnervação. A taxa de remoção da glicose em resposta à insulina exógena após 28 dias de desnervação foi significantemente superior à do controle e àquelas observadas após 3 e 7 dias da desnervação. Esses resultados sugerem que a imobilização por desnervação interfere não só no metabolismo da glicose no músculo esquelético envolvido como também em outros tecidos.

  1. Changes in muscle cell metabolism and mechanotransduction are associated with myopathic phenotype in a mouse model of collagen VI deficiency.

    Directory of Open Access Journals (Sweden)

    Sara De Palma

    Full Text Available This study identifies metabolic and protein phenotypic alterations in gastrocnemius, tibialis anterior and diaphragm muscles of Col6a1(-/- mice, a model of human collagen VI myopathies. All three muscles of Col6a1(-/- mice show some common changes in proteins involved in metabolism, resulting in decreased glycolysis and in changes of the TCA cycle fluxes. These changes lead to a different fate of α-ketoglutarate, with production of anabolic substrates in gastrocnemius and tibialis anterior, and with lipotoxicity in diaphragm. The metabolic changes are associated with changes of proteins involved in mechanotransduction at the myotendineous junction/costameric/sarcomeric level (TN-C, FAK, ROCK1, troponin I fast and in energy metabolism (aldolase, enolase 3, triose phosphate isomerase, creatine kinase, adenylate kinase 1, parvalbumin, IDH1 and FASN. Together, these change may explain Ca(2+ deregulation, impaired force development, increased muscle-relaxation-time and fiber damage found in the mouse model as well as in patients. The severity of these changes differs in the three muscles (gastrocnemiusmuscle morphology.

  2. Neuroimaging of Muscle Pain in Humans

    Directory of Open Access Journals (Sweden)

    David M. Niddam

    2009-06-01

    Full Text Available Neuroimaging has provided important information on how acute and chronic pain is processed in the human brain. The pain experience is now known to be the final product of activity in distributed networks consisting of multiple cortical and subcortical areas. Due to the complex nature of the pain experience, a single cerebral representation of pain does not exist. Instead, pain depends on the context in which it is experienced and is generated through variable expression of the different aspects of pain in conjunction with modulatory influences. While considerable data have been generated about the supraspinal organization of cutaneous pain, little is known about how nociceptive information from musculoskeletal tissue is processed in the brain. This is in spite of the fact that pain from musculoskeletal tissue is more frequently encountered in clinical practice, poses a bigger diagnostic problem and is insufficiently treated. Differences are known to exist between acute pain from cutaneous and muscular tissue in both psychophysical responses as well as in physiological characteristics. The 2 tissue types also differ in pain sensitivity to the same stimuli and in their response to analgesic substances. In this review, characteristics of acute and chronic muscle pain will be presented together with a brief overview of the methods of induction and psychophysical assessment of muscle pain. Results from the neuroimaging literature concerned with phasic and tonic muscle pain will be reviewed.

  3. Myofibre damage in human skeletal muscle

    DEFF Research Database (Denmark)

    Crameri, R M; Aagaard, P; Qvortrup, K

    2007-01-01

    Disruption to proteins within the myofibre after a single bout of unaccustomed eccentric exercise is hypothesized to induce delayed onset of muscle soreness and to be associated with an activation of satellite cells. This has been shown in animal models using electrical stimulation but not in hum......Disruption to proteins within the myofibre after a single bout of unaccustomed eccentric exercise is hypothesized to induce delayed onset of muscle soreness and to be associated with an activation of satellite cells. This has been shown in animal models using electrical stimulation...... but not in humans using voluntary exercise. Untrained males (n=8, range 22-27 years) performed 210 maximal eccentric contractions with each leg on an isokinetic dynamometer, voluntarily (VOL) with one leg and electrically induced (ES) with the other leg. Assessments from the skeletal muscle were obtained prior......, a significant disruption of cytoskeletal proteins (desmin) and a rise of myogenic growth factors (myogenin) occurred only in ES. Intracellular disruption and destroyed Z-lines were markedly more pronounced in ES (40%) compared with VOL (10%). Likewise, the increase in satellite cell markers [neural cell...

  4. Neuroendocrine regulation of human bone metabolism

    NARCIS (Netherlands)

    Vlug, A.G.

    2015-01-01

    The skeleton is perhaps the most multifunctional part of our body. It not only provides outer strength, a protective shell and enables locomotion, but it also hosts the bone marrow and serves many metabolic and endocrine functions. This thesis investigates two aspects of human bone metabolism,

  5. The human metabolic reconstruction Recon 1 directs hypotheses of novel human metabolic functions

    Science.gov (United States)

    2011-01-01

    Background Metabolic network reconstructions formalize our knowledge of metabolism. Gaps in these networks pinpoint regions of metabolism where biological components and functions are "missing." At the same time, a major challenge in the post genomic era involves characterisation of missing biological components to complete genome annotation. Results We used the human metabolic network reconstruction RECON 1 and established constraint-based modelling tools to uncover novel functions associated with human metabolism. Flux variability analysis identified 175 gaps in RECON 1 in the form of blocked reactions. These gaps were unevenly distributed within metabolic pathways but primarily found in the cytosol and often caused by compounds whose metabolic fate, rather than production, is unknown. Using a published algorithm, we computed gap-filling solutions comprised of non-organism specific metabolic reactions capable of bridging the identified gaps. These candidate solutions were found to be dependent upon the reaction environment of the blocked reaction. Importantly, we showed that automatically generated solutions could produce biologically realistic hypotheses of novel human metabolic reactions such as of the fate of iduronic acid following glycan degradation and of N-acetylglutamate in amino acid metabolism. Conclusions The results demonstrate how metabolic models can be utilised to direct hypotheses of novel metabolic functions in human metabolism; a process that we find is heavily reliant upon manual curation and biochemical insight. The effectiveness of a systems approach for novel biochemical pathway discovery in mammals is demonstrated and steps required to tailor future gap filling algorithms to mammalian metabolic networks are proposed. PMID:21962087

  6. The Caveolin-3 P104L mutation of LGMD-1C leads to disordered glucose metabolism in muscle cells.

    Science.gov (United States)

    Deng, Yu Feng; Huang, Yi Yuan; Lu, Wen Sheng; Huang, Yuan Heng; Xian, Jing; Wei, Hong Qiao; Huang, Qin

    2017-04-29

    Caveolin-3 (CAV3) is a muscle specific protein that plays an important role in maintaining muscle health and glucose homeostasis in vivo. A novel autosomal dominant form of LGMD-1C in humans is due to a P104L mutation within the coding sequence of the human CAV3 gene. The mechanism by which the LGMD-1C mutation leads to muscle weakness remains unknown. Our objective was to determine whether muscle weakness was related to the imbalance of glucose metabolism. We found that when the P104L mutation was transiently transfected into C2C12 cells, there was decreased glucose uptake and glycogen synthesis after insulin stimulation. Immunoblotting analysis showed that the P104L mutation resulted in decreased expression of CAV3, CAV1 and pAkt. Confocal immunomicroscopy indicated that the P104L mutation reduced CAV3 and GLUT4 in the cell membrane, which accumulated mainly near the nucleus. This work is the first report of an association between muscle weakness due to LGMD-1C and energy metabolism. The P104L mutation led to a decrease in C2C12 muscle glucose uptake and glycogen synthesis and may be involved in the pathogenesis of LGMD-1C. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Endocrine regulation of fetal skeletal muscle growth: impact on future metabolic health

    Science.gov (United States)

    Brown, Laura D.

    2014-01-01

    Establishing sufficient skeletal muscle mass is essential for lifelong metabolic health. The intrauterine environment is a major determinant of the muscle mass that is present for the life course of an individual, because muscle fiber number is set at the time of birth. Thus, a compromised intrauterine environment from maternal nutrient restriction or placental insufficiency that restricts development of muscle fiber number can have permanent effects on the amount of muscle an individual will live with. Reduced muscle mass due to fewer muscle fibers persists even after compensatory or “catch up” postnatal growth occurs. Furthermore, muscle hypertrophy can only partially compensate for this limitation in fiber number. Compelling associations link low birth weight and decreased muscle mass to future insulin resistance, which can drive the development of the metabolic syndrome and type 2 diabetes, and risk for cardiovascular events later in life. There are gaps in knowledge about the origins of reduced muscle growth at the cellular level and how these patterns are set during fetal development. By understanding the nutrient and endocrine regulation of fetal skeletal muscle growth and development, we can direct research efforts towards improving muscle growth early in life in order to prevent the development of chronic metabolic disease later in life. PMID:24532817

  8. Muscle carnosine metabolism and beta-alanine supplementation in relation to exercise and training.

    Science.gov (United States)

    Derave, Wim; Everaert, Inge; Beeckman, Sam; Baguet, Audrey

    2010-03-01

    Carnosine is a dipeptide with a high concentration in mammalian skeletal muscle. It is synthesized by carnosine synthase from the amino acids L-histidine and beta-alanine, of which the latter is the rate-limiting precursor, and degraded by carnosinase. Recent studies have shown that the chronic oral ingestion of beta-alanine can substantially elevate (up to 80%) the carnosine content of human skeletal muscle. Interestingly, muscle carnosine loading leads to improved performance in high-intensity exercise in both untrained and trained individuals. Although carnosine is not involved in the classic adenosine triphosphate-generating metabolic pathways, this suggests an important role of the dipeptide in the homeostasis of contracting muscle cells, especially during high rates of anaerobic energy delivery. Carnosine may attenuate acidosis by acting as a pH buffer, but improved contractile performance may also be obtained by improved excitation-contraction coupling and defence against reactive oxygen species. High carnosine concentrations are found in individuals with a high proportion of fast-twitch fibres, because these fibres are enriched with the dipeptide. Muscle carnosine content is lower in women, declines with age and is probably lower in vegetarians, whose diets are deprived of beta-alanine. Sprint-trained athletes display markedly high muscular carnosine, but the acute effect of several weeks of training on muscle carnosine is limited. High carnosine levels in elite sprinters are therefore either an important genetically determined talent selection criterion or a result of slow adaptation to years of training. beta-Alanine is rapidly developing as a popular ergogenic nutritional supplement for athletes worldwide, and the currently available scientific literature suggests that its use is evidence based. However, many aspects of the supplement, such as the potential side effects and the mechanism of action, require additional and thorough investigation by the

  9. Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects

    DEFF Research Database (Denmark)

    Davegårdh, Cajsa; Broholm, Christa; Perfilyev, Alexander

    2017-01-01

    subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects. CONCLUSIONS: Our study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic...... is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects. METHODS: We used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA......-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic...

  10. Gender differences in skeletal muscle substrate metabolism - molecular mechanisms and insulin sensitivity

    DEFF Research Database (Denmark)

    Lundsgaard, Annemarie; Kiens, Bente

    2014-01-01

    higher insulin sensitivity of female skeletal muscle can be related to gender-specific regulation of molecular metabolism will be topic for discussion. Gender differences in muscle fiber type distribution and substrate availability to and in skeletal muscle are highly relevant for substrate metabolism......It has become increasingly apparent that substrate metabolism is subject to gender-specific regulation, and the aim of this review is to outline the available evidence of molecular gender differences in glucose and lipid metabolism of skeletal muscle. Female sex has been suggested to have...... a favorable effect on glucose homeostasis, and the available evidence from hyperinsulinemic-euglycemic clamp studies is summarized to delineate whether there is a gender difference in whole-body insulin sensitivity and in particular insulin-stimulated glucose uptake of skeletal muscle. Whether an eventual...

  11. Specificity of insulin signalling in human skeletal muscle as revealed by small interfering RNA.

    Science.gov (United States)

    Krook, A; Zierath, J R

    2009-07-01

    Insulin action on metabolically active tissues is a complex process involving positive and negative feedback regulation to control whole body glucose homeostasis. At the cellular level, glucose and lipid metabolism, as well as protein synthesis, are controlled through canonical insulin signalling cascades. The discovery of small interfering RNA (siRNA) allows for the molecular dissection of critical components of the regulation of metabolic and gene regulatory events in insulin-sensitive tissues. The application of siRNA to tissues of human origin allows for the molecular dissection of the mechanism(s) regulating glucose and lipid metabolism. Penetration of the pathways controlling insulin action in human tissue may aid in discovery efforts to develop diabetes prevention and treatment strategies. This review will focus on the use of siRNA to validate critical regulators controlling insulin action in human skeletal muscle, a key organ important for the control of whole body insulin-mediated glucose uptake and metabolism.

  12. Conjugated linoleic acid or omega 3 fatty acids increase mitochondrial biosynthesis and metabolism in skeletal muscle cells

    Directory of Open Access Journals (Sweden)

    Vaughan Roger A

    2012-10-01

    Full Text Available Abstract Background Polyunsaturated fatty acids are popular dietary supplements advertised to contribute to weight loss by increasing fat metabolism in liver, but the effects on overall muscle metabolism are less established. We evaluated the effects of conjugated linoleic acid (CLA or combination omega 3 on metabolic characteristics in muscle cells. Methods Human rhabdomyosarcoma cells were treated with either DMSO control, or CLA or combination omega 3 for 24 or 48 hours. RNA was determined using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR. Mitochondrial content was determined using flow cytometry and immunohistochemistry. Metabolism was quantified by measuring extracellular acidification and oxygen consumption rates. Results Omega 3 significantly induced metabolic genes as well as oxidative metabolism (oxygen consumption, glycolytic capacity (extracellular acidification, and metabolic rate compared with control. Both treatments significantly increased mitochondrial content. Conclusion Omega 3 fatty acids appear to enhance glycolytic, oxidative, and total metabolism. Moreover, both omega 3 and CLA treatment significantly increase mitochondrial content compared with control.

  13. "Nutraceuticals" in relation to human skeletal muscle and exercise.

    Science.gov (United States)

    Deane, Colleen S; Wilkinson, Daniel J; Phillips, Bethan E; Smith, Kenneth; Etheridge, Timothy; Atherton, Philip J

    2017-04-01

    Skeletal muscles have a fundamental role in locomotion and whole body metabolism, with muscle mass and quality being linked to improved health and even lifespan. Optimizing nutrition in combination with exercise is considered an established, effective ergogenic practice for athletic performance. Importantly, exercise and nutritional approaches also remain arguably the most effective countermeasure for muscle dysfunction associated with aging and numerous clinical conditions, e.g., cancer cachexia, COPD, and organ failure, via engendering favorable adaptations such as increased muscle mass and oxidative capacity. Therefore, it is important to consider the effects of established and novel effectors of muscle mass, function, and metabolism in relation to nutrition and exercise. To address this gap, in this review, we detail existing evidence surrounding the efficacy of a nonexhaustive list of macronutrient, micronutrient, and "nutraceutical" compounds alone and in combination with exercise in relation to skeletal muscle mass, metabolism (protein and fuel), and exercise performance (i.e., strength and endurance capacity). It has long been established that macronutrients have specific roles and impact upon protein metabolism and exercise performance, (i.e., protein positively influences muscle mass and protein metabolism), whereas carbohydrate and fat intakes can influence fuel metabolism and exercise performance. Regarding novel nutraceuticals, we show that the following ones in particular may have effects in relation to 1 ) muscle mass/protein metabolism: leucine, hydroxyl β-methylbutyrate, creatine, vitamin-D, ursolic acid, and phosphatidic acid; and 2 ) exercise performance: (i.e., strength or endurance capacity): hydroxyl β-methylbutyrate, carnitine, creatine, nitrates, and β-alanine. Copyright © 2017 the American Physiological Society.

  14. Coordinated balancing of muscle oxidative metabolism through PGC-1{alpha} increases metabolic flexibility and preserves insulin sensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Summermatter, Serge [Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel (Switzerland); Troxler, Heinz [Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University Children' s Hospital, University of Zurich, Steinwiesstrasse 75, CH-8032 Zurich (Switzerland); Santos, Gesa [Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel (Switzerland); Handschin, Christoph, E-mail: christoph.handschin@unibas.ch [Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel (Switzerland)

    2011-04-29

    Highlights: {yields} PGC-1{alpha} enhances muscle oxidative capacity. {yields} PGC-1{alpha} promotes concomitantly positive and negative regulators of lipid oxidation. {yields} Regulator abundance enhances metabolic flexibility and balances oxidative metabolism. {yields} Balanced oxidation prevents detrimental acylcarnitine and ROS generation. {yields} Absence of detrimental metabolites preserves insulin sensitivity -- Abstract: The peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha} (PGC-1{alpha}) enhances oxidative metabolism in skeletal muscle. Excessive lipid oxidation and electron transport chain activity can, however, lead to the accumulation of harmful metabolites and impair glucose homeostasis. Here, we investigated the effect of over-expression of PGC-1{alpha} on metabolic control and generation of insulin desensitizing agents in extensor digitorum longus (EDL), a muscle that exhibits low levels of PGC-1{alpha} in the untrained state and minimally relies on oxidative metabolism. We demonstrate that PGC-1{alpha} induces a strictly balanced substrate oxidation in EDL by concomitantly promoting the transcription of activators and inhibitors of lipid oxidation. Moreover, we show that PGC-1{alpha} enhances the potential to uncouple oxidative phosphorylation. Thereby, PGC-1{alpha} boosts elevated, yet tightly regulated oxidative metabolism devoid of side products that are detrimental for glucose homeostasis. Accordingly, PI3K activity, an early phase marker for insulin resistance, is preserved in EDL muscle. Our findings suggest that PGC-1{alpha} coordinately coactivates the simultaneous transcription of gene clusters implicated in the positive and negative regulation of oxidative metabolism and thereby increases metabolic flexibility. Thus, in mice fed a normal chow diet, over-expression of PGC-1{alpha} does not alter insulin sensitivity and the metabolic adaptations elicited by PGC-1{alpha} mimic the beneficial effects of endurance training

  15. Pronounced effects of acute endurance exercise on gene expression in resting and exercising human skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Milène Catoire

    Full Text Available Regular physical activity positively influences whole body energy metabolism and substrate handling in exercising muscle. While it is recognized that the effects of exercise extend beyond exercising muscle, it is unclear to what extent exercise impacts non-exercising muscles. Here we investigated the effects of an acute endurance exercise bouts on gene expression in exercising and non-exercising human muscle. To that end, 12 male subjects aged 44-56 performed one hour of one-legged cycling at 50% W(max. Muscle biopsies were taken from the exercising and non-exercising leg before and immediately after exercise and analyzed by microarray. One-legged cycling raised plasma lactate, free fatty acids, cortisol, noradrenalin, and adrenalin levels. Surprisingly, acute endurance exercise not only caused pronounced gene expression changes in exercising muscle but also in non-exercising muscle. In the exercising leg the three most highly induced genes were all part of the NR4A family. Remarkably, many genes induced in non-exercising muscle were PPAR targets or related to PPAR signalling, including PDK4, ANGPTL4 and SLC22A5. Pathway analysis confirmed this finding. In conclusion, our data indicate that acute endurance exercise elicits pronounced changes in gene expression in non-exercising muscle, which are likely mediated by changes in circulating factors such as free fatty acids. The study points to a major influence of exercise beyond the contracting muscle.

  16. Effect of creatine on aerobic and anaerobic metabolism in skeletal muscle in swimmers.

    Science.gov (United States)

    Thompson, C H; Kemp, G J; Sanderson, A L; Dixon, R M; Styles, P; Taylor, D J; Radda, G K

    1996-09-01

    To examine the effect of a relatively low dose of creatine on skeletal muscle metabolism and oxygen supply in a group of training athletes. 31P magnetic resonance and near-infrared spectroscopy were used to study calf muscle metabolism in a group of 10 female members of a university swimming team. Studies were performed before and after a six week period of training during which they took either 2 g creatine daily or placebo. Calf muscle metabolism and creatine/choline ratios were studied in resting muscle, during plantar flexion exercise (10-15 min), and during recovery from exercise. There was no effect of creatine on metabolite ratios at rest or on metabolism during exercise and recovery from exercise. Muscle oxygen supply and exercise performance were not improved by creatine if compared to placebo treated subjects. Oral creatine supplementation at 2 g daily has no effect on muscle creatine concentration, muscle oxygen supply or muscle aerobic or anaerobic metabolism during endurance exercise.

  17. Myogenin regulates exercise capacity and skeletal muscle metabolism in the adult mouse.

    Directory of Open Access Journals (Sweden)

    Jesse M Flynn

    2010-10-01

    Full Text Available Although skeletal muscle metabolism is a well-studied physiological process, little is known about how it is regulated at the transcriptional level. The myogenic transcription factor myogenin is required for skeletal muscle development during embryonic and fetal life, but myogenin's role in adult skeletal muscle is unclear. We sought to determine myogenin's function in adult muscle metabolism. A Myog conditional allele and Cre-ER transgene were used to delete Myog in adult mice. Mice were analyzed for exercise capacity by involuntary treadmill running. To assess oxidative and glycolytic metabolism, we performed indirect calorimetry, monitored blood glucose and lactate levels, and performed histochemical analyses on muscle fibers. Surprisingly, we found that Myog-deleted mice performed significantly better than controls in high- and low-intensity treadmill running. This enhanced exercise capacity was due to more efficient oxidative metabolism during low- and high-intensity exercise and more efficient glycolytic metabolism during high-intensity exercise. Furthermore, Myog-deleted mice had an enhanced response to long-term voluntary exercise training on running wheels. We identified several candidate genes whose expression was altered in exercise-stressed muscle of mice lacking myogenin. The results suggest that myogenin plays a critical role as a high-level transcriptional regulator to control the energy balance between aerobic and anaerobic metabolism in adult skeletal muscle.

  18. Metabolomics Reveals Protection of Resveratrol in Diet-Induced Metabolic Risk Factors in Abdominal Muscle.

    Science.gov (United States)

    Chen, Guoyou; Ye, Guozhu; Zhang, Xinbo; Liu, Xiaoxiao; Tu, Yingfeng; Ye, Zengjie; Liu, Jincheng; Guo, Qi; Wang, Zhiguo; Wang, Lin; Dong, Sijun; Fan, Yuhua

    2018-02-07

    Abdominal obesity is recognized as the main reason of metabolic syndrome, which is closely related to disordered skeletal and/or abdominal muscle metabolic functions. Metabolomics is a comprehensive assessment system in biological metabolites. The aim of our present study is to investigate the diet-induced metabolic risk factors by metabolic in the abdominal muscles and clarify the relationship between atheroprotective effects of Resveratrol (Rev) and abdominal muscles metabolic components during the development of atherosclerosis. The mice were randomly divided into three groups including normal group (N), high fat diet (HFD or H) group and high fat diet with Rev treated group (HR). GC-MS combined with pattern recognition approaches were employed to obtain comprehensive metabolic signatures and related differential metabolites after 24 week HFD feeding. Oil Red O staining and Electron microscopy technology (EMT) were employed to detect the size of fatty plaques and intracellular lipid accumulation, respectively. The result indicated that 22 types of metabolites in the abdominal muscles were obviously altered by HFD feeding group. Moreover, Rev treatment obviously increased 11 different kinds of metabolites, most of which were involved in the carbohydrate, amino acid and lipid metabolisms. Importantly, these elevated different metabolites were involved in pathways mainly related to galactose metabolism, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism in abdominal muscles. Oil Red O staining and Electron microscopy showed less lipid accumulation in the lesions and decreased intracellular lipid deposition in the foam cells in HR group. We concluded that Rev produced a beneficial effect partially by modulating multiple metabolism pathways and metabolites in the abdominal muscles, which may provide a new protective mechanism of Rev on the progression of atherosclerosis. These notably changed metabolites might be potential biomarkers

  19. Glucose transporter expression in human skeletal muscle fibers

    DEFF Research Database (Denmark)

    Gaster, M; Handberg, A; Beck-Nielsen, H

    2000-01-01

    amplification (TSA) technique to detect the localization of glucose transporter expression in human skeletal muscle. We found expression of GLUT-1, GLUT-3, and GLUT-4 in developing human muscle fibers showing a distinct expression pattern. 1) GLUT-1 is expressed in human skeletal muscle cells during gestation......, but its expression is markedly reduced around birth and is further reduced to undetectable levels within the first year of life; 2) GLUT-3 protein expression appears at 18 wk of gestation and disappears after birth; and 3) GLUT-4 protein is diffusely expressed in muscle cells throughout gestation, whereas...

  20. Cryopreservation of human skeletal muscle impairs mitochondrial function

    DEFF Research Database (Denmark)

    Larsen, Steen; Wright-Paradis, C; Gnaiger, E

    2012-01-01

    Previous studies have investigated if cryopreservation is a viable approach for functional mitochondrial analysis. Different tissues have been studied, and conflicting results have been published. The aim of the present study was to investigate if mitochondria in human skeletal muscle maintain...... functionality after long term cryopreservation (1 year). Skeletal muscle samples were preserved in dimethyl sulfoxide (DMSO) for later analysis. Human skeletal muscle fibres were thawed and permeabilised with saponin, and mitochondrial respiration was measured by high-resolution respirometry. The capacity...... of oxidative phosphorylation was significantly (P cryopreserved human skeletal muscle samples. Cryopreservation impaired respiration with substrates linked to Complex I more than for Complex II (P

  1. Localization of nitric oxide synthase in human skeletal muscle

    DEFF Research Database (Denmark)

    Frandsen, Ulrik; Lopez-Figueroa, M.; Hellsten, Ylva

    1996-01-01

    The present study investigated the cellular localization of the neuronal type I and endothelial type III nitric oxide synthase in human skeletal muscle. Type I NO synthase immunoreactivity was found in the sarcolemma and the cytoplasm of all muscle fibres. Stronger immunoreactivity was expressed...... I NO synthase immunoreactivity and NADPH diaphorase activity. Type III NO synthase immunoreactivity was observed both in the endothelium of larger vessels and of microvessels. The results establish that human skeletal muscle expresses two different constitutive isoforms of NO synthase in different...... endothelium is consistent with a role for NO in the control of blood flow in human skeletal muscle....

  2. Muscle-tendon mechanics explain unexpected effects of exoskeleton assistance on metabolic rate during walking.

    Science.gov (United States)

    Jackson, Rachel W; Dembia, Christopher L; Delp, Scott L; Collins, Steven H

    2017-06-01

    The goal of this study was to gain insight into how ankle exoskeletons affect the behavior of the plantarflexor muscles during walking. Using data from previous experiments, we performed electromyography-driven simulations of musculoskeletal dynamics to explore how changes in exoskeleton assistance affected plantarflexor muscle-tendon mechanics, particularly for the soleus. We used a model of muscle energy consumption to estimate individual muscle metabolic rate. As average exoskeleton torque was increased, while no net exoskeleton work was provided, a reduction in tendon recoil led to an increase in positive mechanical work performed by the soleus muscle fibers. As net exoskeleton work was increased, both soleus muscle fiber force and positive mechanical work decreased. Trends in the sum of the metabolic rates of the simulated muscles correlated well with trends in experimentally observed whole-body metabolic rate (R2=0.9), providing confidence in our model estimates. Our simulation results suggest that different exoskeleton behaviors can alter the functioning of the muscles and tendons acting at the assisted joint. Furthermore, our results support the idea that the series tendon helps reduce positive work done by the muscle fibers by storing and returning energy elastically. We expect the results from this study to promote the use of electromyography-driven simulations to gain insight into the operation of muscle-tendon units and to guide the design and control of assistive devices. © 2017. Published by The Company of Biologists Ltd.

  3. Systematic Sensitivity Analysis of Metabolic Controllers During Reductions in Skeletal Muscle Blood Flow

    Science.gov (United States)

    Radhakrishnan, Krishnan; Cabrera, Marco

    2000-01-01

    An acute reduction in oxygen delivery to skeletal muscle is generally associated with profound derangements in substrate metabolism. Given the complexity of the human bioenergetic system and its components, it is difficult to quantify the interaction of cellular metabolic processes to maintain ATP homeostasis during stress (e.g., hypoxia, ischemia, and exercise). Of special interest is the determination of mechanisms relating tissue oxygenation to observed metabolic responses at the tissue, organ, and whole body levels and the quantification of how changes in oxygen availability affect the pathways of ATP synthesis and their regulation. In this study, we apply a previously developed mathematical model of human bioenergetics to study effects of ischemia during periods of increased ATP turnover (e.g., exercise). By using systematic sensitivity analysis the oxidative phosphorylation rate was found to be the most important rate parameter affecting lactate production during ischemia under resting conditions. Here we examine whether mild exercise under ischemic conditions alters the relative importance of pathways and parameters previously obtained.

  4. Gender differences in skeletal muscle substrate metabolism - molecular mechanisms and insulin sensitivity

    Directory of Open Access Journals (Sweden)

    Anne-Marie eLundsgaard

    2014-11-01

    Full Text Available It has become increasingly apparent that substrate metabolism is subject to gender specific regulation, and the aim of this review is to outline the available evidence of molecular gender differences in glucose and lipid metabolism of skeletal muscle. Female sex has been suggested to have a favorable effect on glucose homeostasis, and the available evidence from hyperinsulinemic-euglycemic clamp studies is summarized to delineate whether there is a gender difference in whole body insulin sensitivity and in particular insulin-stimulated glucose uptake of skeletal muscle. Whether an eventual higher insulin sensitivity of female skeletal muscle can be related to gender specific regulation of molecular metabolism will be topic for discussion. Gender differences in muscle fiber type distribution and substrate availability to and in skeletal muscle are highly relevant for substrate metabolism in men and women. In particular, the molecular machinery for glucose and fatty acid oxidative and storage capacities in skeletal muscle and its implications for substrate utilization during metabolic situations of daily living are discussed, emphasizing their relevance for substrate choice in the fed and fasted state, and during periods of physical activity and recovery. Together, handling of carbohydrate and lipids and regulation of their utilization in skeletal muscle have implications for whole body glucose homeostasis in men and women. 17-β estradiol is the most important female sex hormone, and the identification of estradiol receptors in skeletal muscle has opened for a role in regulation of substrate metabolism. Also, higher levels of circulating adipokines as adiponectin and leptin in women and their implications for muscle metabolism will be considered.

  5. The human metabolic reconstruction Recon 1 directs hypotheses of novel human metabolic functions

    Directory of Open Access Journals (Sweden)

    Thiele Ines

    2011-10-01

    Full Text Available Abstract Background Metabolic network reconstructions formalize our knowledge of metabolism. Gaps in these networks pinpoint regions of metabolism where biological components and functions are "missing." At the same time, a major challenge in the post genomic era involves characterisation of missing biological components to complete genome annotation. Results We used the human metabolic network reconstruction RECON 1 and established constraint-based modelling tools to uncover novel functions associated with human metabolism. Flux variability analysis identified 175 gaps in RECON 1 in the form of blocked reactions. These gaps were unevenly distributed within metabolic pathways but primarily found in the cytosol and often caused by compounds whose metabolic fate, rather than production, is unknown. Using a published algorithm, we computed gap-filling solutions comprised of non-organism specific metabolic reactions capable of bridging the identified gaps. These candidate solutions were found to be dependent upon the reaction environment of the blocked reaction. Importantly, we showed that automatically generated solutions could produce biologically realistic hypotheses of novel human metabolic reactions such as of the fate of iduronic acid following glycan degradation and of N-acetylglutamate in amino acid metabolism. Conclusions The results demonstrate how metabolic models can be utilised to direct hypotheses of novel metabolic functions in human metabolism; a process that we find is heavily reliant upon manual curation and biochemical insight. The effectiveness of a systems approach for novel biochemical pathway discovery in mammals is demonstrated and steps required to tailor future gap filling algorithms to mammalian metabolic networks are proposed.

  6. The effect of the muscle environment on the regenerative capacity of human skeletal muscle stem cells.

    Science.gov (United States)

    Meng, Jinhong; Bencze, Maximilien; Asfahani, Rowan; Muntoni, Francesco; Morgan, Jennifer E

    2015-01-01

    Muscle stem cell transplantation is a possible treatment for muscular dystrophy. In addition to the intrinsic properties of the stem cells, the local and systemic environment plays an important role in determining the fate of the grafted cells. We therefore investigated the effect of modulating the host muscle environment in different ways (irradiation or cryoinjury or a combination of irradiation and cryoinjury) in two immunodeficient mouse strains (mdx nude and recombinase-activating gene (Rag)2-/γ chain-/C5-) on the regenerative capacity of two types of human skeletal muscle-derived stem cell (pericytes and CD133+ cells). Human skeletal muscle-derived pericytes or CD133+ cells were transplanted into muscles of either mdx nude or recombinase-activating gene (Rag)2-/γ chain-/C5- host mice. Host muscles were modulated prior to donor cell transplantation by either irradiation, or cryoinjury, or a combination of irradiation and cryoinjury. Muscles were analysed four weeks after transplantation, by staining transverse cryostat sections of grafted muscles with antibodies to human lamin A/C, human spectrin, laminin and Pax 7. The number of nuclei and muscle fibres of donor origin and the number of satellite cells of both host and donor origin were quantified. Within both host strains transplanted intra-muscularly with both donor cell types, there were significantly more nuclei and muscle fibres of donor origin in host muscles that had been modulated by cryoinjury, or irradiation+cryoinjury, than by irradiation alone. Irradiation has no additive effects in further enhancing the transplantation efficiency than cryodamage. Donor pericytes did not give rise to satellite cells. However, using CD133+ cells as donor cells, there were significantly more nuclei, muscle fibres, as well as satellite cells of donor origin in Rag2-/γ chain-/C5- mice than mdx nude mice, when the muscles were injured by either cryodamage or irradiation+cryodamage. Rag2-/γ chain-/C5- mice are a

  7. PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle.

    Science.gov (United States)

    Hatazawa, Yukino; Tadaishi, Miki; Nagaike, Yuta; Morita, Akihito; Ogawa, Yoshihiro; Ezaki, Osamu; Takai-Igarashi, Takako; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Kamei, Yasutomi; Miura, Shinji

    2014-01-01

    Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA) metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain α-keto acid dehydrogenase (BCKDH), which catabolize BCAA. The expression of BCKDH kinase (BCKDK), which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism.

  8. PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Yukino Hatazawa

    Full Text Available Peroxisome proliferator-activated receptor (PPAR γ coactivator 1α (PGC-1α is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT 2, branched-chain α-keto acid dehydrogenase (BCKDH, which catabolize BCAA. The expression of BCKDH kinase (BCKDK, which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism.

  9. Characterization of the Human Skeletal Muscle Proteome by One-dimensional Gel Electrophoresis and HPLC-ESI-MS/MS

    DEFF Research Database (Denmark)

    Højlund, Kurt; Yi, Zhengping; Hwang, Hyonson

    2008-01-01

    Changes in protein abundance in skeletal muscle are central to a large number of metabolic and other disorders, including, and perhaps most commonly, insulin resistance. Proteomics analysis of human muscle is an important approach for gaining insight into the biochemical basis for normal...... mass spectrometry, we identified 954 different proteins in human vastus lateralis muscle obtained from three healthy, nonobese subjects. In addition to a large number of isoforms of contractile proteins, we detected all proteins involved in the major pathways of glucose and lipid metabolism in skeletal...... muscle. Mitochondrial proteins accounted for 22% of all proteins identified, including 55 subunits of the respiratory complexes I-V. Moreover, a number of enzymes involved in endocrine and metabolic signaling pathways as well as calcium homeostasis were identified. These results provide the most...

  10. Human myotubes from myoblast cultures undergoing senescence exhibit defects in glucose and lipid metabolism

    DEFF Research Database (Denmark)

    Nehlin, Jan O; Just, Marlene; Rustan, Arild C

    2011-01-01

    Adult stem cells are known to have a finite replication potential. Muscle biopsy-derived human satellite cells (SCs) were grown at different passages and differentiated to human myotubes in culture to analyze the functional state of various carbohydrate and lipid metabolic pathways...... number and could be explained by reduced incorporation into diacyl- and triacylglycerols. The levels of long-chain acyl-CoA esters decreased with increased passage number. Late-passage, non-proliferating, myoblast cultures showed strong senescence-associated β-galactosidase activity indicating...... that the observed metabolic defects accompany the induction of a senescent state. The main function of SCs is regeneration and skeletal muscle-build up. Thus, the metabolic defects observed during aging of SC-derived myotubes could have a role in sarcopenia, the gradual age-related loss of muscle mass and strength....

  11. Thermodynamic significance of human basal metabolism

    Science.gov (United States)

    Wang, Cuncheng

    1993-06-01

    The human basal state, a non-equilibrium steady state, is analysed in this paper in the light of the First and Second Laws of Thermodynamics whereby the thermodynamic significance of the basal metabolic rate and its distinction to the dissipation function and exergy loss are identified. The analysis demonstrates the correct expression of the effects of the blood flow on the heat balance in a human-body bio-heat model and the relationship between the basal metabolic rate and the blood perfusion.

  12. In vivo Phosphoproteome of Human Skeletal Muscle Revealed by Phosphopeptide Enrichment and HPLC-ESI-MS/MS

    DEFF Research Database (Denmark)

    Højlund, Kurt; Bowen, Benjamin P; Hwang, Hyonson

    2009-01-01

    Protein phosphorylation plays an essential role in signal transduction pathways that regulate substrate and energy metabolism, contractile function, and muscle mass in human skeletal muscle. Abnormal phosphorylation of signaling enzymes has been identified in insulin resistant muscle using...... volunteers. Trypsin digestion of 3-5 mg human skeletal muscle protein was followed by phosphopeptide enrichment using SCX and TiO2. The resulting phosphopeptides were analyzed by HPLC-ESI-MS/MS. Using this unbiased approach, we identified 306 distinct in vivo phosphorylation sites in 127 proteins, including...... phosphoepitope-specific antibodies, but its role in other skeletal muscle disorders remains largely unknown. This may be in part due to insufficient knowledge of relevant targets. Here, we therefore present the first large-scale in vivo phosphoproteomic study of human skeletal muscle from 3 lean, healthy...

  13. miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle

    Directory of Open Access Journals (Sweden)

    Duo Zhang

    2016-07-01

    Full Text Available Understanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC. Short-term high-fat diet (HFD feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα, which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control.

  14. Skeletal muscle interleukin-6 regulates metabolic factors in iWAT during HFD and exercise training

    DEFF Research Database (Denmark)

    Knudsen, Jakob Grunnet; Bertholdt, Lærke; Joensen, Ella

    2015-01-01

    OBJECTIVE: To investigate the role of skeletal muscle (SkM) interleukin (IL)-6 in the regulation of adipose tissue metabolism. METHODS: Muscle-specific IL-6 knockout (IL-6 MKO) and IL-6(loxP/loxP) (Floxed) mice were subjected to standard rodent diet (Chow), high-fat diet (HFD), or HFD in combinat...

  15. Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

    DEFF Research Database (Denmark)

    Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han

    2015-01-01

    in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription...

  16. TXNIP Regulates Peripheral Glucose Metabolism in Humans

    Science.gov (United States)

    Parikh, Hemang; Carlsson, Emma; Chutkow, William A; Johansson, Lovisa E; Storgaard, Heidi; Poulsen, Pernille; Saxena, Richa; Ladd, Christine; Schulze, P. Christian; Mazzini, Michael J; Jensen, Christine Bjørn; Krook, Anna; Björnholm, Marie; Tornqvist, Hans; Zierath, Juleen R; Ridderstråle, Martin; Altshuler, David; Lee, Richard T; Vaag, Allan; Groop, Leif C; Mootha, Vamsi K

    2007-01-01

    Background Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. Methods and Findings We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. Conclusions TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic β-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM. PMID:17472435

  17. TXNIP regulates peripheral glucose metabolism in humans.

    Directory of Open Access Journals (Sweden)

    Hemang Parikh

    2007-05-01

    Full Text Available Type 2 diabetes mellitus (T2DM is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure.We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM.TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.

  18. Altered tryptophan metabolism in human meningioma.

    Science.gov (United States)

    Talari, Noble Kumar; Panigrahi, Manas; Madigubba, Sailaja; Challa, Sundaram; Phanithi, Prakash Babu

    2016-10-01

    Meningiomas are the neoplasms that arise from the arachnoid cells of the meninges. It was reported that cancer cells escape from immune system through the metabolism of an aromatic essential amino acid tryptophan (TRP) via Kynurenine (KYN) pathway. However, the role of TRP metabolites such as, 5-Hydroxy tryptophan (5-HTP), 5-Hydroxy tryptamine (5-HT), N-acetyl serotonin (NAS), Melatonin (MEL), KYN, N-acetyl tryptamine, 5-Hydroxy indole acetic acid (5-HIAA) and 5-Methoxy indole acetic acid is not yet evaluated in human meningioma. Therefore, in the current study we have evaluated the levels of TRP and its metabolites in the progression of human meningioma using tumor biopsy samples and autopsy control meninges with Reverse Phase-HPLC. We here report that TRP metabolism favors towards KYN pathway in human meningioma and it could be due to increased indoleamine 2,3-dioxygenase 2 levels as we found its m-RNA levels to be up regulated in human meningioma. We observed significant increase in KYN and 5HIAA levels and significant decrease in TRP, 5-HTP, 5-HT, NAS and MEL levels in meningioma compared to control meninges. Since TRP metabolites regulate inducible nitric oxide synthase (INOS) gene expression and thereby nitric oxide (NO) production, we have also evaluated the INOS and NO levels. The INOS and NO levels were up regulated in human meningioma. The present data corroborates with existing data on TRP metabolism in tumor progression and may serve to target TRP metabolism as a therapeutic intervention.

  19. The mechanistic bases of the power-time relationship: muscle metabolic responses and relationships to muscle fibre type.

    Science.gov (United States)

    Vanhatalo, Anni; Black, Matthew I; DiMenna, Fred J; Blackwell, Jamie R; Schmidt, Jakob Friis; Thompson, Christopher; Wylie, Lee J; Mohr, Magni; Bangsbo, Jens; Krustrup, Peter; Jones, Andrew M

    2016-08-01

    The power-asymptote (critical power; CP) of the hyperbolic power-time relationship for high-intensity exercise defines a threshold between steady-state and non-steady-state exercise intensities and the curvature constant (W') indicates a fixed capacity for work >CP that is related to a loss of muscular efficiency. The present study reports novel evidence on the muscle metabolic underpinnings of CP and W' during whole-body exercise and their relationships to muscle fibre type. We show that the W' is not correlated with muscle fibre type distribution and that it represents an elevated energy contribution from both oxidative and glycolytic/glycogenolytic metabolism. We show that there is a positive correlation between CP and highly oxidative type I muscle fibres and that muscle metabolic steady-state is attainable CP. Our findings indicate a mechanistic link between the bioenergetic characteristics of muscle fibre types and the power-time relationship for high-intensity exercise. We hypothesized that: (1) the critical power (CP) will represent a boundary separating steady-state from non-steady-state muscle metabolic responses during whole-body exercise and (2) that the CP and the curvature constant (W') of the power-time relationship for high-intensity exercise will be correlated with type I and type IIx muscle fibre distributions, respectively. Four men and four women performed a 3 min all-out cycling test for the estimation of CP and constant work rate (CWR) tests slightly >CP until exhaustion (Tlim ), slightly CP Tlim isotime to test the first hypothesis. Eleven men performed 3 min all-out tests and donated muscle biopsies to test the second hypothesis. Below CP, muscle [PCr] [42.6 ± 7.1 vs. 49.4 ± 6.9 mmol (kg d.w.)(-1) ], [La(-) ] [34.8 ± 12.6 vs. 35.5 ± 13.2 mmol (kg d.w.)(-1) ] and pH (7.11 ± 0.08 vs. 7.10 ± 0.11) remained stable between ∼12 and 24 min (P > 0.05 for all), whereas these variables changed with time >CP such that

  20. Human Metabolism and Interactions of Deployment-Related Chemicals

    National Research Council Canada - National Science Library

    Hodgson, Ernest

    2003-01-01

    This study examines the human-metabolism and metabolic interactions of a subset of deployment-related chemicals, including chlorpyrifos, DEET, permethrin, pyridostigmine bromide, and sulfur mustard metabolites...

  1. Lipid storage changes in human skeletal muscle during detraining

    Directory of Open Access Journals (Sweden)

    Rong eZhu

    2015-11-01

    Full Text Available Exercise training is known to increase intramuscular triglyceride content in both trained and untrained legs. The purpose of the study was to determine the changes of intramyocellular lipids (IMCL and extramyocellular lipids (EMCL of both trained and untrained legs during detraining. We measured both IMCL and EMCL levels in previously trained versus untrained legs during 4-weeks of detraining after 6-weeks of strength training. Eight young men (aged 21.4+/- 1.4 years trained their vastus lateralis muscle in one leg using a dynamometer, whereas the contralateral leg served as untrained control. Muscle cross-sectional area (CSA, IMCL, EMCL, total creatine (creatine+phophocreatine of extensor (vastus lateralis muscles were assessed using magnetic resonance imaging (MRI and proton magnetic resonance spectra (1H-MRS before training, 3 days after and 28 days after the last bout of training. CSA was increased in both legs by Day 3 after training, and was still high at Day 28 post-training; IMCL increased in both legs by Day 3 after training, then decreased at Day 28 post-training only in the untrained leg; EMCL shows no significant change by Day 3 after training, but at Day 28 post-training has increased in the trained leg and decreased in the untrained leg; total creatine did not change significantly. Conclusion: Decreases of IMCL and EMCL storages in previously untrained leg during detraining indicates an ectopic influence on tissue lipid storage by different metabolic demand among tissues in the same human body.

  2. Systemic down-regulation of delta-9 desaturase promotes muscle oxidative metabolism and accelerates muscle function recovery following nerve injury.

    Directory of Open Access Journals (Sweden)

    Ghulam Hussain

    Full Text Available The progressive deterioration of the neuromuscular axis is typically observed in degenerative conditions of the lower motor neurons, such as amyotrophic lateral sclerosis (ALS. Neurodegeneration in this disease is associated with systemic metabolic perturbations, including hypermetabolism and dyslipidemia. Our previous gene profiling studies on ALS muscle revealed down-regulation of delta-9 desaturase, or SCD1, which is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. Interestingly, knocking out SCD1 gene is known to induce hypermetabolism and stimulate fatty acid beta-oxidation. Here we investigated whether SCD1 deficiency can affect muscle function and its restoration in response to injury. The genetic ablation of SCD1 was not detrimental per se to muscle function. On the contrary, muscles in SCD1 knockout mice shifted toward a more oxidative metabolism, and enhanced the expression of synaptic genes. Repressing SCD1 expression or reducing SCD-dependent enzymatic activity accelerated the recovery of muscle function after inducing sciatic nerve crush. Overall, these findings provide evidence for a new role of SCD1 in modulating the restorative potential of skeletal muscles.

  3. Systemic Down-Regulation of Delta-9 Desaturase Promotes Muscle Oxidative Metabolism and Accelerates Muscle Function Recovery following Nerve Injury

    Science.gov (United States)

    Henriques, Alexandre; Lequeu, Thiebault; Rene, Frederique; Bindler, Françoise; Dirrig-Grosch, Sylvie; Oudart, Hugues; Palamiuc, Lavinia; Metz-Boutigue, Marie-Helene; Dupuis, Luc; Marchioni, Eric; Gonzalez De Aguilar, Jose-Luis; Loeffler, Jean-Philippe

    2013-01-01

    The progressive deterioration of the neuromuscular axis is typically observed in degenerative conditions of the lower motor neurons, such as amyotrophic lateral sclerosis (ALS). Neurodegeneration in this disease is associated with systemic metabolic perturbations, including hypermetabolism and dyslipidemia. Our previous gene profiling studies on ALS muscle revealed down-regulation of delta-9 desaturase, or SCD1, which is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. Interestingly, knocking out SCD1 gene is known to induce hypermetabolism and stimulate fatty acid beta-oxidation. Here we investigated whether SCD1 deficiency can affect muscle function and its restoration in response to injury. The genetic ablation of SCD1 was not detrimental per se to muscle function. On the contrary, muscles in SCD1 knockout mice shifted toward a more oxidative metabolism, and enhanced the expression of synaptic genes. Repressing SCD1 expression or reducing SCD-dependent enzymatic activity accelerated the recovery of muscle function after inducing sciatic nerve crush. Overall, these findings provide evidence for a new role of SCD1 in modulating the restorative potential of skeletal muscles. PMID:23785402

  4. Molecular aging and rejuvenation of human muscle stem cells

    DEFF Research Database (Denmark)

    Carlson, Morgan E; Suetta, Charlotte; Conboy, Michael J

    2009-01-01

    Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans....... Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth...... factor beta (TGF-beta)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular...

  5. Severe Obesity: Evidence for a Deranged Metabolic Program in Skeletal Muscle?

    OpenAIRE

    Houmard, Joseph A; Pories, Walter J; Dohm, G Lynis

    2012-01-01

    Severe obesity is increasing at a disproportionate rate compared to milder grade obesity. Our research group has obtained evidence indicative of an “obesity metabolic program” in the skeletal muscle of severely obese individuals which may be genetically or epigenetically determined. We believe this represents a paradigm shift in thinking about metabolic regulation in obesity.

  6. Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism

    Directory of Open Access Journals (Sweden)

    Carles Lerin

    2016-10-01

    Conclusions: Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.

  7. The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism

    DEFF Research Database (Denmark)

    Szekeres, Ferenc; Chadt, Alexandra; Tom, Robby Z

    2012-01-01

    The Rab-GTPase-activating protein TBC1D1 has emerged as a novel candidate involved in metabolic regulation. Our aim was to determine whether TBC1D1 is involved in insulin as well as energy-sensing signals controlling skeletal muscle metabolism. TBC1D1-deficient congenic B6.SJL-Nob1.10 (Nob1.10(SJ...

  8. Purinergic receptors expressed in human skeletal muscle fibres

    DEFF Research Database (Denmark)

    Bornø, A; Ploug, Thorkil; Bune, L T

    2012-01-01

    Purinergic receptors are present in most tissues and thought to be involved in various signalling pathways, including neural signalling, cell metabolism and local regulation of the microcirculation in skeletal muscles. The present study aims to determine the distribution and intracellular content...... of purinergic receptors in skeletal muscle fibres in patients with type 2 diabetes and age-matched controls. Muscle biopsies from vastus lateralis were obtained from six type 2 diabetic patients and seven age-matched controls. Purinergic receptors were analysed using light and confocal microscopy...

  9. Skeletal muscle lipid metabolism in exercise and insulin resistance

    DEFF Research Database (Denmark)

    Kiens, Bente

    2006-01-01

    Lipids as fuel for energy provision originate from different sources: albumin-bound long-chain fatty acids (LCFA) in the blood plasma, circulating very-low-density lipoproteins-triacylglycerols (VLDL-TG), fatty acids from triacylglycerol located in the muscle cell (IMTG), and possibly fatty acids...... of insulin resistance in skeletal muscle, including possible molecular mechanisms involved, is discussed....

  10. Enhanced muscle glucose metabolism after exercise in the rat

    DEFF Research Database (Denmark)

    Garetto, L P; Richter, Erik; Goodman, M N

    1984-01-01

    Thirty minutes after a treadmill run, glucose utilization and glycogen synthesis in perfused rat skeletal muscle are enhanced due to an increase in insulin sensitivity (Richter et al., J. Clin. Invest. 69: 785-793, 1982). The exercise used in these studies was of moderate intensity, and muscle gl...

  11. Pasture-feeding of Charolais steers influences skeletal muscle metabolism and gene expression.

    Science.gov (United States)

    Cassar-Malek, I; Jurie, C; Bernard, C; Barnola, I; Micol, D; Hocquette, J-F

    2009-10-01

    Extensive beef production systems on pasture are promoted to improve animal welfare and beef quality. This study aimed to compare the influence on muscle characteristics of two management approaches representative of intensive and extensive production systems. One group of 6 Charolais steers was fed maize-silage indoors and another group of 6 Charolais steers grazed on pasture. Activities of enzymes representative of glycolytic and oxidative (Isocitrate dehydrogenase [ICDH], citrate synthase [CS], hydroxyacyl-CoA dehydrogenase [HAD]) muscle metabolism were assessed in Rectus abdominis (RA) and Semitendinosus (ST) muscles. Activities of oxidative enzymes ICDH, CS and HAD were higher in muscles from grazing animals demonstrating a plasticity of muscle metabolism according to the production and feeding system. Gene expression profiling in RA and ST muscles was performed on both production groups using a multi-tissue bovine cDNA repertoire. Variance analysis showed an effect of the muscle type and of the production system on gene expression (Psystem was established, of which 149 genes corresponded to identified genes. They were classified according to their gene function annotation mainly in the "protein metabolism and modification", "signal transduction", "cell cycle", "developmental processes" and "muscle contraction" biological processes. Selenoprotein W was found to be underexpressed in pasture-fed animals and could be proposed as a putative gene marker of the grass-based system. In conclusion, enzyme-specific adaptations and gene expression modifications were observed in response to the production system and some of them could be candidates for grazing or grass-feeding traceability.

  12. Pneumatic Muscles Actuated Lower-Limb Orthosis Model Verification with Actual Human Muscle Activation Patterns

    Directory of Open Access Journals (Sweden)

    Dzahir M.A.M

    2017-01-01

    Full Text Available A review study was conducted on existing lower-limb orthosis systems for rehabilitation which implemented pneumatic muscle type of actuators with the aim to clarify the current and on-going research in this field. The implementation of pneumatic artificial muscle will play an important role for the development of the advanced robotic system. In this research a derivation model for the antagonistic mono- and bi-articular muscles using pneumatic artificial muscles of a lower limb orthosis will be verified with actual human’s muscle activities models. A healthy and young male 29 years old subject with height 174cm and weight 68kg was used as a test subject. Two mono-articular muscles Vastus Medialis (VM and Vastus Lateralis (VL were selected to verify the mono-articular muscle models and muscle synergy between anterior muscles. Two biarticular muscles Rectus Femoris (RF and Bicep Femoris (BF were selected to verify the bi-articular muscle models and muscle co-contraction between anterior-posterior muscles. The test was carried out on a treadmill with a speed of 4.0 km/h, which approximately around 1.25 m/s for completing one cycle of walking motion. The data was collected for about one minute on a treadmill and 20 complete cycles of walking motion were successfully recorded. For the evaluations, the mathematical model obtained from the derivation and the actual human muscle activation patterns obtained using the surface electromyography (sEMG system were compared and analysed. The results shown that, high correlation values ranging from 0.83 up to 0.93 were obtained in between the derivation model and the actual human muscle’s model for both mono- and biarticular muscles. As a conclusion, based on the verification with the sEMG muscle activities data and its correlation values, the proposed derivation models of the antagonistic mono- and bi-articular muscles were suitable to simulate and controls the pneumatic muscles actuated lower limb

  13. Growth hormone enhances effects of endurance training on oxidative muscle metabolism in elderly women

    DEFF Research Database (Denmark)

    Lange, K H; Isaksson, F; Juul, A

    2000-01-01

    The present study investigated whether recombinant human (rh) growth hormone (GH) combined with endurance training would have a larger effect on oxidative capacity, metabolism, and body fat than endurance training alone. Sixteen healthy, elderly women, aged 75 yr, performed closely monitored...... endurance training on a cycle ergometer over 12 wk. rhGH was given in a randomized, double-blinded, placebo-controlled design in addition to the training program. GH administration resulted in a doubling of serum insulin-like growth factor I levels. With endurance training, peak oxygen uptake increased...... in the two subjects receiving rhGH. In conclusion, rhGH adds to the effects of endurance training on muscle oxidative enzymes and causes a reduction in body fat in elderly women....

  14. The chemical disruption of human metabolism.

    Science.gov (United States)

    Genuis, Stephen J; Kyrillos, Edmond

    2017-09-01

    Recent evidence highlights the reality of unprecedented human exposure to toxic chemical agents found throughout our environment - in our food and water supply, in the air we breathe, in the products we apply to our skin, in the medical and dental materials placed into our bodies, and even within the confines of the womb. With biomonitoring confirming the widespread bioaccumulation of myriad toxicants among population groups, expanding research continues to explore the pathobiological impact of these agents on human metabolism. This review was prepared by assessing available medical and scientific literature from Medline as well as by reviewing several books, toxicology journals, government publications, and conference proceedings. The format of a traditional integrated review was chosen. Toxicant exposure and accrual has been linked to numerous biochemical and pathophysiological mechanisms of harm. Some toxicants effect metabolic disruption via multiple mechanisms. As a primary causative determinant of chronic disease, toxicant exposures induce metabolic disruption in myriad ways, which consequently result in varied clinical manifestations, which are then categorized by health providers into innumerable diagnoses. Chemical disruption of human metabolism has become an etiological determinant of much illness throughout the lifecycle, from neurodevelopmental abnormalities in-utero to dementia in the elderly.

  15. In vivo (31)P MRS study of skeletal muscle metabolism in patients with postpolio residual paralysis.

    Science.gov (United States)

    Sharma, Uma; Kumar, Virendra; Wadhwa, Sanjay; Jagannathan, Naranamangalan R

    2007-02-01

    The muscle metabolism of at-rest patients with varying degrees of postpolio residual paralysis (PPRP) was studied and compared with that of controls using in vivo phosphorus magnetic resonance spectroscopy. The phosphocreatine (PCr)/inorganic phosphate (Pi) and PCr/adenosine triphosphate ratios were lower in patients than in controls. Reduction in PCr/Pi suggests abnormalities in oxidative phosphorylation. A significant increase was observed in the phosphomonoester/PCr ratio in patients, indicating the accumulation of intermediary compounds of the glycolytic pathway. Furthermore, the phosphodiester/PCr ratio was also significantly increased in patients. In general, the observed changes in metabolite ratios were found to be related to the degree of residual paralysis, suggesting that metabolic changes are secondary to chronic neurogenic processes. These metabolic alterations appear to be the possible cause of energy deficit and underlying muscle fatigue in PPRP patients. The present results provide an insight into the metabolic impairment and degree of muscle damage in patients with PPRP.

  16. Modulation of human muscle spindle discharge by arterial pulsations - functional effects and consequences

    NARCIS (Netherlands)

    Birznieks, I.; Boonstra, T.W.; Macefield, V.G.

    2012-01-01

    Arterial pulsations are known to modulate muscle spindle firing; however, the physiological significance of such synchronised modulation has not been investigated. Unitary recordings were made from 75 human muscle spindle afferents innervating the pretibial muscles. The modulation of muscle spindle

  17. Observational Study on the Occurrence of Muscle Spindles in Human Digastric and Mylohyoideus Muscles

    Directory of Open Access Journals (Sweden)

    Daniele Saverino

    2014-01-01

    Full Text Available Although the occurrence of muscle spindles (MS is quite high in most skeletal muscles of humans, few MS, or even absence, have been reported in digastric and mylohyoideus muscles. Even if this condition is generally accepted and quoted in many papers and books, observational studies are scarce and based on histological sections of a low number of specimens. The aim of the present study is to confirm previous data, assessing MS number in a sample of digastric and mylohyoideus muscles. We investigated 11 digastric and 6 mylohyoideus muscles from 13 donors. Muscle samples were embedded in paraffin wax, cross-sectioned in a rostrocaudal direction, and stained using haematoxylin-eosin. A mean of 5.1 ± 1.1 (range 3–7 MS was found in digastric muscles and mean of 0.5 ± 0.8 (range 0–2 in mylohyoideus muscles. A significant difference (P<0.001 was found with the control sample, confirming the correctness of the histological procedure. Our results support general belief that the absolute number of spindles is sparse in digastric and mylohyoideus muscles. External forces, such as food resistance during chewing or gravity, do not counteract jaw-opening muscles. It is conceivable that this condition gives them a limited proprioceptive importance and a reduced need for having specific receptors as MS.

  18. Simulating the physiology of athletes during endurance sports events: Modelling human energy conversion and metabolism

    NARCIS (Netherlands)

    Beek, J.H.G.M. van; Supandi, F.; Gavai, A.K.; Graaf, A.A. de; Binsl, T.W.; Hettling, H.

    2011-01-01

    The human physiological system is stressed to its limits during endurance sports competition events.We describe a whole body computational model for energy conversion during bicycle racing. About 23 per cent of the metabolic energy is used for muscle work, the rest is converted to heat. We

  19. Effect of lipopolysaccharide on inflammation and insulin action in human muscle.

    Directory of Open Access Journals (Sweden)

    Hanyu Liang

    Full Text Available Accumulating evidence from animal studies suggest that chronic elevation of circulating intestinal-generated lipopolysaccharide (LPS (i.e., metabolic endotoxemia could play a role in the pathogenesis of insulin resistance. However, the effect of LPS in human muscle is unclear. Moreover, it is unknown whether blockade/down regulation of toll-like receptor (TLR4 can prevent the effect of LPS on insulin action and glucose metabolism in human muscle cells. In the present study we compared plasma LPS concentration in insulin resistant [obese non-diabetic and obese type 2 diabetic (T2DM] subjects versus lean individuals. In addition, we employed a primary human skeletal muscle cell culture system to investigate the effect of LPS on glucose metabolism and whether these effects are mediated via TLR4. Obese non-diabetic and T2DM subjects had significantly elevated plasma LPS and LPS binding protein (LBP concentrations. Plasma LPS (r = -0.46, P = 0.005 and LBP (r = -0.49, P = 0.005 concentrations negatively correlated with muscle insulin sensitivity (M. In human myotubes, LPS increased JNK phosphorylation and MCP-1 and IL-6 gene expression. This inflammatory response led to reduced insulin-stimulated IRS-1, Akt and AS160 phosphorylation and impaired glucose transport. Both pharmacologic blockade of TLR4 with TAK-242, and TLR4 gene silencing, suppressed the inflammatory response and insulin resistance caused by LPS in human muscle cells. Taken together, these findings suggest that elevations in plasma LPS concentration found in obese and T2DM subjects could play a role in the pathogenesis of insulin resistance and that antagonists of TLR4 may improve insulin action in these individuals.

  20. The Regulation of Muscle Structure and Metabolism by Mio/dChREBP in Drosophila.

    Directory of Open Access Journals (Sweden)

    Grzegorz L Polak

    Full Text Available All cells require energy to perform their specialized functions. Muscle is particularly sensitive to the availability of nutrients due to the high-energy requirement for muscle contraction. Therefore the ability of muscle cells to obtain, store and utilize energy is essential for the function of these cells. Mio, the Drosophila homolog of carbohydrate response element binding protein (ChREBP, has recently been identified as a nutrient responsive transcription factor important for triglyceride storage in the fly fat body. However, the function of Mio in muscle is unknown. In this study, we characterized the role of Mio in controlling muscle function and metabolism. Decreasing Mio levels using RNAi specifically in muscle results in increased thorax glycogen storage. Adult Mio-RNAi flies also have a flight defect due to altered myofibril shape and size in the indirect flight muscles as shown by electron microscopy. Myofibril size is also decreased in flies just before emerging from their pupal cases, suggesting a role for Mio in myofibril development. Together, these data indicate a novel role for Mio in controlling muscle structure and metabolism and may provide a molecular link between nutrient availability and muscle function.

  1. Supplementing healthy rats with a high-niacin dose has no effect on muscle fiber distribution and muscle metabolic phenotype.

    Science.gov (United States)

    Scholz, Kristen; Kynast, Anna Marie; Couturier, Aline; Mooren, Frank-Christoph; Krüger, Karsten; Most, Erika; Eder, Klaus; Ringseis, Robert

    2014-08-01

    It was recently shown that niacin prevents the obesity-induced type I to type II fiber switching in skeletal muscle of obese rats and favors the development of a more oxidative metabolic phenotype and thereby increases whole body utilization of fatty acids. Whether niacin also causes type II to type I fiber switching in skeletal muscle of healthy rats has not been investigated yet. Thus, the present study aimed to investigate whether niacin supplementation influences fiber distribution and metabolic phenotype of different skeletal muscles with a distinct type I-to-type II fiber ratio in healthy rats. Twenty-four male, 10-week-old Sprague-Dawley rats were randomly assigned into two groups of 12 rats each and fed either a control diet with 30 mg supplemented niacin/kg diet (control group) or a high-niacin diet with 780 mg supplemented niacin/kg diet (high-niacin group). After 27 days of treatment, the percentage number of type I fibers in rectus femoris, gastrocnemius, and tibialis anterior muscles was 5-10% greater in the niacin group than in the control group, but did not differ between groups in soleus and vastus intermedius muscles. Transcript levels of genes encoding transcription factors regulating fiber switching, fiber-specific myosin heavy chain isoforms, and proteins involved in fatty acid utilization, oxidative phosphorylation, and angiogenesis did not differ between groups. The results show that niacin has only negligible effects on fiber distribution and its regulation as well as the metabolic phenotype of skeletal muscle in healthy rats.

  2. Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle.

    Science.gov (United States)

    Laurens, Claire; Bourlier, Virginie; Mairal, Aline; Louche, Katie; Badin, Pierre-Marie; Mouisel, Etienne; Montagner, Alexandra; Marette, André; Tremblay, Angelo; Weisnagel, John S; Guillou, Hervé; Langin, Dominique; Joanisse, Denis R; Moro, Cedric

    2016-12-06

    Lipid droplets (LD) play a central role in lipid homeostasis by controlling transient fatty acid (FA) storage and release from triacylglycerols stores, while preventing high levels of cellular toxic lipids. This crucial function in oxidative tissues is altered in obesity and type 2 diabetes. Perilipin 5 (PLIN5) is a LD protein whose mechanistic and causal link with lipotoxicity and insulin resistance has raised controversies. We investigated here the physiological role of PLIN5 in skeletal muscle upon various metabolic challenges. We show that PLIN5 protein is elevated in endurance-trained (ET) subjects and correlates with muscle oxidative capacity and whole-body insulin sensitivity. When overexpressed in human skeletal muscle cells to recapitulate the ET phenotype, PLIN5 diminishes lipolysis and FA oxidation under basal condition, but paradoxically enhances FA oxidation during forskolin- and contraction- mediated lipolysis. Moreover, PLIN5 partly protects muscle cells against lipid-induced lipotoxicity. In addition, we demonstrate that down-regulation of PLIN5 in skeletal muscle inhibits insulin-mediated glucose uptake under normal chow feeding condition, while paradoxically improving insulin sensitivity upon high-fat feeding. These data highlight a key role of PLIN5 in LD function, first by finely adjusting LD FA supply to mitochondrial oxidation, and second acting as a protective factor against lipotoxicity in skeletal muscle.

  3. [Aspartate aminotransferase--key enzyme in the human systemic metabolism].

    Science.gov (United States)

    Otto-Ślusarczyk, Dagmara; Graboń, Wojciech; Mielczarek-Puta, Magdalena

    2016-03-16

    Aspartate aminotransferase is an organ-nonspecific enzyme located in many tissues of the human body where it catalyzes reversible reaction of transamination. There are two aspartate aminotransferase isoforms--cytoplasmic (AST1) and mitochondrial (AST2), that usually occur together and interact with each other metabolically. Both isoforms are homodimers containing highly conservative regions responsible for catalytic properties of enzyme. The common feature of all aspartate aminotransfeses is Lys - 259 residue covalent binding with prosthetic group - pyridoxal phosphate. The differences in the primary structure of AST isoforms determine their physico-chemical, kinetic and immunological properties. Because of the low concentration of L-aspartate (L-Asp) in the blood, AST is the only enzyme, which supply of this amino acid as a substrate for many metabolic processes, such as urea cycle or purine and pyrimidine nucleotides in the liver, synthesis of L-arginine in the kidney and purine nucleotide cycle in the brain and the skeletal muscle. AST is also involved in D-aspartate production that regulates the metabolic activity at the auto-, para- and endocrine level. Aspartate aminotransferase is a part of the malate-aspartate shuttle in the myocardium, is involved in gluconeogenesis in the liver and kidney, glyceroneogenesis in the adipose tissue, and synthesis of neurotransmitters and neuro-glial pathway in the brain. Recently, the significant role of AST in glutaminolysis - normal metabolic pathway in tumor cells, was demonstrated. The article is devoted the role of AST, known primarily as a diagnostic liver enzyme, in metabolism of various human tissues and organs.

  4. Aspartate aminotransferase – key enzyme in the human systemic metabolism

    Directory of Open Access Journals (Sweden)

    Dagmara Otto-Ślusarczyk

    2016-03-01

    Full Text Available Aspartate aminotransferase is an organ - nonspecific enzyme located in many tissues of the human body where it catalyzes reversible reaction of transamination. There are two aspartate aminotransferase isoforms - cytoplasmic (AST1 and mitochondrial (AST2, that usually occur together and interact with each other metabolically. Both isoforms are homodimers containing highly conservative regions responsible for catalytic properties of enzyme. The common feature of all aspartate aminotransfeses is Lys – 259 residue covalent binding with prosthetic group - pyridoxal phosphate. The differences in the primary structure of AST isoforms determine their physico-chemical, kinetic and immunological properties. Because of the low concentration of L-aspartate (L-Asp in the blood, AST is the only enzyme, which supply of this amino acid as a substrate for many metabolic processes, such as urea cycle or purine and pyrimidine nucleotides in the liver, synthesis of L-arginine in the kidney and purine nucleotide cycle in the brain and the skeletal muscle. AST is also involved in D-aspartate production that regulates the metabolic activity at the auto-, para- and endocrine level. Aspartate aminotransferase is a part of the malate-aspartate shuttle in the myocardium, is involved in gluconeogenesis in the liver and kidney, glyceroneogenesis in the adipose tissue, and synthesis of neurotransmitters and neuro-glial pathway in the brain. Recently, the significant role of AST in glutaminolysis - normal metabolic pathway in tumor cells, was demonstrated. The article is devoted the role of AST, known primarily as a diagnostic liver enzyme, in metabolism of various human tissues and organs.

  5. Regulation of exercise-induced lipid metabolism in skeletal muscle

    DEFF Research Database (Denmark)

    Jordy, Andreas Børsting; Kiens, Bente

    2014-01-01

    Exercise increases the utilization of lipids in muscle. The sources of lipids are long-chain fatty acids taken up from the plasma and fatty acids released from stores of intramuscular triacylglycerol by the action of intramuscular lipases. In the present review, we focus on the role of fatty acid....../muscle contractions. This occurs independently of AMP-activated protein kinase, and data suggest that Ca(2+)-related signalling is responsible. The FAT/CD36 has an important role; long-chain fatty acid uptake is markedly decreased in FAT/CD36 knockout mice during contractions/exercise compared with wild-type control...... mice. In skeletal muscle, 98% of the lipase activity is accounted for by adipose triglyceride lipase and hormone-sensitive lipase. Give that inhibition or knockout of hormone-sensitive lipase does not impair lipolysis in muscle during contraction, the data point to an important role of adipose...

  6. Factors regulating fat oxidation in human skeletal muscle

    DEFF Research Database (Denmark)

    Kiens, Bente; Alsted, Thomas Junker; Jeppesen, Jacob

    2011-01-01

    In modern societies, oversupply of calories leads to obesity and chronic metabolic stress, which may lead to development of disease. Oversupply of calories is often associated with elevated plasma lipid concentrations and accumulation of lipids in skeletal muscle leading to decreased insulin sens...

  7. Quantification of subcellular glycogen in resting human muscle: granule size, number, and location.

    Science.gov (United States)

    Marchand, I; Chorneyko, K; Tarnopolsky, M; Hamilton, S; Shearer, J; Potvin, J; Graham, T E

    2002-11-01

    A few qualitative investigations suggested that location of muscle glycogen (G) granules in specific sites may be associated with distinct metabolic roles. Similarly, it has been suggested that the acid-soluble and -insoluble G fractions (macro- and proglycogen, respectively) are different metabolic pools and also could exist as separate entities. We employed a transmission electron microscopic technique to quantify subcellular G particle size, number, and location in human vastus lateralis biopsies of 11 resting men. The intra- and interobserver variability for the various measures was generally etam and followed a continuous, normal distribution. This implies that proglycogen is not a distinct entity, but rather that pro- and macroglycogen are divisions of smaller and larger molecules. These results demonstrate a compartmentalized pattern of subcellular G deposition in human skeletal muscle for both the size and density of granules.

  8. Phytoestrogen Metabolism by Adult Human Gut Microbiota

    Directory of Open Access Journals (Sweden)

    Pilar Gaya

    2016-08-01

    Full Text Available Phytoestrogens are plant-derived polyphenols with a structure similar to human estrogens. The three main groups of phytoestrogens, isoflavones, ellagitannins, and lignans, are transformed into equol, urolithins, and enterolignans, respectively, by bacteria. These metabolites have more estrogenic/antiestrogenic and antioxidant activities than their precursors, and they are more bioavailable. The aim of this study was to analyze the metabolism of isoflavones, lignans and ellagitannins by gut microbiota, and to study the possible correlation in the metabolism of these three groups of phytoestrogens. In vitro fermentation experiments were performed with feces samples from 14 healthy adult volunteers, and metabolite formation was measured by HPLC-PAD and HPLC-ESI/MS. Only the microbiota of one subject produced equol, while most of them showed production of O-desmethylangolensin (O-DMA. Significant inter-subject differences were observed in the metabolism of dihydrodaidzein and dihydrogenistein, while the glucoside isoflavones and their aglycones showed less variability, except for glycitin. Most subjects produced urolithins M-5 and E. Urolithin D was not detected, while uroltithin B was found in half of the individuals analyzed, and urolithins A and C were detected in two and four subjects, respectively. Enterolactone was found in all subjects, while enterodiol only appeared in five. Isoflavone metabolism could be correlated with the metabolism of lignans and ellagitannins. However, the metabolism of ellagitannins and lignans could not be correlated. This the first study where the metabolism of the three groups together of phytoestrogen, isoflavones, lignans, and ellagitannins by gut microbiota is analyzed.

  9. Increasing NAD synthesis in muscle via nicotinamide phosphoribosyltransferase is not sufficient to promote oxidative metabolism.

    Science.gov (United States)

    Frederick, David W; Davis, James G; Dávila, Antonio; Agarwal, Beamon; Michan, Shaday; Puchowicz, Michelle A; Nakamaru-Ogiso, Eiko; Baur, Joseph A

    2015-01-16

    The NAD biosynthetic precursors nicotinamide mononucleotide and nicotinamide riboside are reported to confer resistance to metabolic defects induced by high fat feeding in part by promoting oxidative metabolism in skeletal muscle. Similar effects are obtained by germ line deletion of major NAD-consuming enzymes, suggesting that the bioavailability of NAD is limiting for maximal oxidative capacity. However, because of their systemic nature, the degree to which these interventions exert cell- or tissue-autonomous effects is unclear. Here, we report a tissue-specific approach to increase NAD biosynthesis only in muscle by overexpressing nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in the salvage pathway that converts nicotinamide to NAD (mNAMPT mice). These mice display a ∼50% increase in skeletal muscle NAD levels, comparable with the effects of dietary NAD precursors, exercise regimens, or loss of poly(ADP-ribose) polymerases yet surprisingly do not exhibit changes in muscle mitochondrial biogenesis or mitochondrial function and are equally susceptible to the metabolic consequences of high fat feeding. We further report that chronic elevation of muscle NAD in vivo does not perturb the NAD/NADH redox ratio. These studies reveal for the first time the metabolic effects of tissue-specific increases in NAD synthesis and suggest that critical sites of action for supplemental NAD precursors reside outside of the heart and skeletal muscle. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Shortening-induced force depression in human adductor pollicis muscle

    NARCIS (Netherlands)

    De Ruiter, C J; De Haan, A; Jones, D A; Sargeant, A J

    1998-01-01

    1. The effects of single isovelocity shortening contractions on force production of the electrically stimulated human adductor pollicis muscle were investigated in seven healthy male subjects. 2. Redeveloped isometric force immediately following isovelocity shortening was always depressed compared

  11. Shortening induced force depression in human adductor pollicis muscle

    NARCIS (Netherlands)

    de Ruiter, C.J.; de Haan, A.; Jones, D.A.; Sargeant, A.J.

    1998-01-01

    1. The effects of single isovelocity shortening contractions on force production of the electrically stimulated human adductor pollicis muscle were investigated in seven healthy male subjects. 2. Redeveloped isometric force immediately following isovelocity shortening was always depressed compared

  12. A minimal dose of electrically induced muscle activity regulates distinct gene signaling pathways in humans with spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Michael A Petrie

    Full Text Available Paralysis after a spinal cord injury (SCI induces physiological adaptations that compromise the musculoskeletal and metabolic systems. Unlike non-SCI individuals, people with spinal cord injury experience minimal muscle activity which compromises optimal glucose utilization and metabolic control. Acute or chronic muscle activity, induced through electrical stimulation, may regulate key genes that enhance oxidative metabolism in paralyzed muscle. We investigated the short and long term effects of electrically induced exercise on mRNA expression of human paralyzed muscle. We developed an exercise dose that activated the muscle for only 0.6% of the day. The short term effects were assessed 3 hours after a single dose of exercise, while the long term effects were assessed after training 5 days per week for at least one year (adherence 81%. We found a single dose of exercise regulated 117 biological pathways as compared to 35 pathways after one year of training. A single dose of electrical stimulation increased the mRNA expression of transcriptional, translational, and enzyme regulators of metabolism important to shift muscle toward an oxidative phenotype (PGC-1α, NR4A3, IFRD1, ABRA, PDK4. However, chronic training increased the mRNA expression of specific metabolic pathway genes (BRP44, BRP44L, SDHB, ACADVL, mitochondrial fission and fusion genes (MFF, MFN1, MFN2, and slow muscle fiber genes (MYH6, MYH7, MYL3, MYL2. These findings support that a dose of electrical stimulation (∼10 minutes/day regulates metabolic gene signaling pathways in human paralyzed muscle. Regulating these pathways early after SCI may contribute to reducing diabetes in people with longstanding paralysis from SCI.

  13. Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis

    Energy Technology Data Exchange (ETDEWEB)

    May, R.C.; Hara, Y.; Kelly, R.A.; Block, K.P.; Buse, M.G.; Mitch, W.E.

    1987-06-01

    Branched-chain amino acid (BCAA) metabolism is frequently abnormal in pathological conditions accompanied by chronic metabolic acidosis. To study how metabolic acidosis affects BCAA metabolism in muscle, rats were gavage fed a 14% protein diet with or without 4 mmol NH/sub 4/Cl x 100 g body wt/sup -1/ x day/sup -1/. Epitrochlearis muscles were incubated with L-(1-/sup 14/C)-valine and L-(1-/sup 14/C)leucine, and rates of decarboxylation, net transamination, and incorporation into muscle protein were measured. Plasma and muscle BCAA levels were lower in acidotic rats. Rates of valine and leucine decarboxylation and net transamination were higher in muscles from acidotic rats; these differences were associated with a 79% increase in the total activity of branched-chain ..cap alpha..-keto acid dehydrogenase and a 146% increase in the activated form of the enzyme. They conclude that acidosis affects the regulation of BCAA metabolism by enhancing flux through the transaminase and by directly stimulating oxidative catabolism through activation of branched-chain ..cap alpha..-keto acid dehydrogenase.

  14. Insulin increases phosphorylation of mitochondrial proteins in human skeletal muscle in vivo

    DEFF Research Database (Denmark)

    Zhao, Xiaolu; Bak, Steffen; Pedersen, Andreas James Thestrup

    2014-01-01

    There is increasing evidence that multiple proteins involved in key regulatory processes in mitochondria are phosphorylated in mammalian tissues. Insulin regulates glucose metabolism by phosphorylation-dependent signaling and has been shown to stimulate ATP synthesis in human skeletal muscle. Here......, we investigated the effect of insulin on the phosphorylation of mitochondrial proteins in human skeletal muscle in vivo. Using a combination of TiO2 phosphopeptide-enrichment, HILIC fractionation, and LC−MS/MS, we compared the phosphoproteomes of isolated mitochondria from skeletal muscle samples...... obtained from healthy individuals before and after 4 h of insulin infusion. In total, we identified 207 phosphorylation sites in 95 mitochondrial proteins. Of these phosphorylation sites, 45% were identified in both basal and insulin-stimulated samples. Insulin caused a 2-fold increase in the number...

  15. Intermuscular force transmission between human plantarflexor muscles in vivo

    DEFF Research Database (Denmark)

    Bojsen-Møller, Jens; Bojsen-Møller, Jens; Schwartz, Sidse

    2010-01-01

    The exact mechanical function of synergist muscles within a human limb in vivo is not well described. Recent studies indicate the existence of a mechanical interaction between muscle actuators that may have functional significance and further play a role for injury mechanisms. The purpose...... of the present study was to investigate if intermuscular force transmission occurs within and between human plantarflexor muscles in vivo. Seven subjects performed four types of either active contractile tasks or passive joint manipulations: passive knee extension, voluntary isometric plantarflexion, voluntary...... task-induced tissue displacement (which is assumed to represent loading) for the plantarflexor muscles [MG, soleus (SOL), and flexor hallucis longus (FHL)]. Selective MG stimulation and passive knee extension resulted in displacement of both the MG and SOL muscles. Minimal displacement of the triceps...

  16. Bionic Humans Using EAP as Artificial Muscles Reality and Challenges

    OpenAIRE

    Yoseph Bar-Cohen

    2004-01-01

    For many years, the idea of a human with bionic muscles immediately conjures up science fiction images of a TV series superhuman character that was implanted with bionic muscles and portrayed with strength and speed far superior to any normal human. As fantastic as this idea may seem, recent developments in electroactive polymers (EAP) may one day make such bionics possible. Polymers that exhibit large displacement in response to stimulation that is other than electrical signa...

  17. Human metabolic network: reconstruction, simulation, and applications in systems biology.

    Science.gov (United States)

    Wu, Ming; Chan, Christina

    2012-03-02

    Metabolism is crucial to cell growth and proliferation. Deficiency or alterations in metabolic functions are known to be involved in many human diseases. Therefore, understanding the human metabolic system is important for the study and treatment of complex diseases. Current reconstructions of the global human metabolic network provide a computational platform to integrate genome-scale information on metabolism. The platform enables a systematic study of the regulation and is applicable to a wide variety of cases, wherein one could rely on in silico perturbations to predict novel targets, interpret systemic effects, and identify alterations in the metabolic states to better understand the genotype-phenotype relationships. In this review, we describe the reconstruction of the human metabolic network, introduce the constraint based modeling approach to analyze metabolic networks, and discuss systems biology applications to study human physiology and pathology. We highlight the challenges and opportunities in network reconstruction and systems modeling of the human metabolic system.

  18. Human muscle satellite cells as targets of Chikungunya virus infection.

    Directory of Open Access Journals (Sweden)

    Simona Ozden

    Full Text Available BACKGROUND: Chikungunya (CHIK virus is a mosquito-transmitted alphavirus that causes in humans an acute infection characterised by fever, polyarthralgia, head-ache, and myalgia. Since 2005, the emergence of CHIK virus was associated with an unprecedented magnitude outbreak of CHIK disease in the Indian Ocean. Clinically, this outbreak was characterized by invalidating poly-arthralgia, with myalgia being reported in 97.7% of cases. Since the cellular targets of CHIK virus in humans are unknown, we studied the pathogenic events and targets of CHIK infection in skeletal muscle. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistology on muscle biopsies from two CHIK virus-infected patients with myositic syndrome showed that viral antigens were found exclusively inside skeletal muscle progenitor cells (designed as satelllite cells, and not in muscle fibers. To evaluate the ability of CHIK virus to replicate in human satellite cells, we assessed virus infection on primary human muscle cells; viral growth was observed in CHIK virus-infected satellite cells with a cytopathic effect, whereas myotubes were essentially refractory to infection. CONCLUSIONS/SIGNIFICANCE: This report provides new insights into CHIK virus pathogenesis, since it is the first to identify a cellular target of CHIK virus in humans and to report a selective infection of muscle satellite cells by a viral agent in humans.

  19. Muscle-driven finite element simulation of human foot movements.

    Science.gov (United States)

    Spyrou, L A; Aravas, N

    2012-01-01

    This paper describes a finite element scheme for realistic muscle-driven simulation of human foot movements. The scheme is used to simulate human ankle plantar flexion. A three-dimensional anatomically detailed finite element model of human foot and lower leg is developed and the idea of generating natural foot movement based entirely on the contraction of the plantar flexor muscles is used. The bones, ligaments, articular cartilage, muscles, tendons, as well as the rest soft tissues of human foot and lower leg are included in the model. A realistic three-dimensional continuum constitutive model that describes the biomechanical behaviour of muscles and tendons is used. Both the active and passive properties of muscle tissue are accounted for. The materials for bones and ligaments are considered as homogeneous, isotropic and linearly elastic, whereas the articular cartilage and the rest soft tissues (mainly fat) are defined as hyperelastic materials. The model is used to estimate muscle tissue deformations as well as stresses and strains that develop in the lower leg muscles during plantar flexion of the ankle. Stresses and strains that develop in Achilles tendon during such a movement are also investigated.

  20. Decellularized Human Skeletal Muscle as Biologic Scaffold for Reconstructive Surgery

    Science.gov (United States)

    Porzionato, Andrea; Sfriso, Maria Martina; Pontini, Alex; Macchi, Veronica; Petrelli, Lucia; Pavan, Piero G.; Natali, Arturo N.; Bassetto, Franco; Vindigni, Vincenzo; De Caro, Raffaele

    2015-01-01

    Engineered skeletal muscle tissues have been proposed as potential solutions for volumetric muscle losses, and biologic scaffolds have been obtained by decellularization of animal skeletal muscles. The aim of the present work was to analyse the characteristics of a biologic scaffold obtained by decellularization of human skeletal muscles (also through comparison with rats and rabbits) and to evaluate its integration capability in a rabbit model with an abdominal wall defect. Rat, rabbit and human muscle samples were alternatively decellularized with two protocols: n.1, involving sodium deoxycholate and DNase I; n.2, trypsin-EDTA and Triton X-NH4OH. Protocol 2 proved more effective, removing all cellular material and maintaining the three-dimensional networks of collagen and elastic fibers. Ultrastructural analyses with transmission and scanning electron microscopy confirmed the preservation of collagen, elastic fibres, glycosaminoglycans and proteoglycans. Implantation of human scaffolds in rabbits gave good results in terms of integration, although recellularization by muscle cells was not completely achieved. In conclusion, human skeletal muscles may be effectively decellularized to obtain scaffolds preserving the architecture of the extracellular matrix and showing mechanical properties suitable for implantation/integration. Further analyses will be necessary to verify the suitability of these scaffolds for in vitro recolonization by autologous cells before in vivo implantation. PMID:26140375

  1. Decellularized Human Skeletal Muscle as Biologic Scaffold for Reconstructive Surgery

    Directory of Open Access Journals (Sweden)

    Andrea Porzionato

    2015-07-01

    Full Text Available Engineered skeletal muscle tissues have been proposed as potential solutions for volumetric muscle losses, and biologic scaffolds have been obtained by decellularization of animal skeletal muscles. The aim of the present work was to analyse the characteristics of a biologic scaffold obtained by decellularization of human skeletal muscles (also through comparison with rats and rabbits and to evaluate its integration capability in a rabbit model with an abdominal wall defect. Rat, rabbit and human muscle samples were alternatively decellularized with two protocols: n.1, involving sodium deoxycholate and DNase I; n.2, trypsin-EDTA and Triton X-NH4OH. Protocol 2 proved more effective, removing all cellular material and maintaining the three-dimensional networks of collagen and elastic fibers. Ultrastructural analyses with transmission and scanning electron microscopy confirmed the preservation of collagen, elastic fibres, glycosaminoglycans and proteoglycans. Implantation of human scaffolds in rabbits gave good results in terms of integration, although recellularization by muscle cells was not completely achieved. In conclusion, human skeletal muscles may be effectively decellularized to obtain scaffolds preserving the architecture of the extracellular matrix and showing mechanical properties suitable for implantation/integration. Further analyses will be necessary to verify the suitability of these scaffolds for in vitro recolonization by autologous cells before in vivo implantation.

  2. On the mechanism by which dietary nitrate improves human skeletal muscle function

    Directory of Open Access Journals (Sweden)

    Charles eAffourtit

    2015-07-01

    Full Text Available Inorganic nitrate is present at high levels in beetroot and celery, and in green leafy vegetables such as spinach and lettuce. Though long believed inert, nitrate can be reduced to nitrite in the human mouth and, further, under hypoxia and/or low pH, to nitric oxide. Dietary nitrate has thus been associated favourably with nitric-oxide-regulated processes including blood flow and energy metabolism. Indeed, the therapeutic potential of dietary nitrate in cardiovascular disease and metabolic syndrome – both ageing-related medical disorders – has attracted considerable recent research interest. We and others have shown that dietary nitrate supplementation lowers the oxygen cost of human exercise, as less respiratory activity appears to be required for a set rate of skeletal muscle work. This striking observation predicts that nitrate benefits the energy metabolism of human muscle, increasing the efficiency of either mitochondrial ATP synthesis and/or of cellular ATP-consuming processes. In this mini-review, we evaluate experimental support for the dietary nitrate effects on muscle bioenergetics and we critically discuss the likelihood of nitric oxide as the molecular mediator of such effects.

  3. Human Satellite Cell Transplantation and Regeneration from Diverse Skeletal Muscles

    Directory of Open Access Journals (Sweden)

    Xiaoti Xu

    2015-09-01

    Full Text Available Identification of human satellite cells that fulfill muscle stem cell criteria is an unmet need in regenerative medicine. This hurdle limits understanding how closely muscle stem cell properties are conserved among mice and humans and hampers translational efforts in muscle regeneration. Here, we report that PAX7 satellite cells exist at a consistent frequency of 2–4 cells/mm of fiber in muscles of the human trunk, limbs, and head. Xenotransplantation into mice of 50–70 fiber-associated, or 1,000–5,000 FACS-enriched CD56+/CD29+ human satellite cells led to stable engraftment and formation of human-derived myofibers. Human cells with characteristic PAX7, CD56, and CD29 expression patterns populated the satellite cell niche beneath the basal lamina on the periphery of regenerated fibers. After additional injury, transplanted satellite cells robustly regenerated to form hundreds of human-derived fibers. Together, these findings conclusively delineate a source of bona-fide endogenous human muscle stem cells that will aid development of clinical applications.

  4. Morphology of muscle attachment sites in the modern human hand does not reflect muscle architecture.

    Science.gov (United States)

    Williams-Hatala, E M; Hatala, K G; Hiles, S; Rabey, K N

    2016-06-23

    Muscle attachment sites (entheses) on dry bones are regularly used by paleontologists to infer soft tissue anatomy and to reconstruct behaviors of extinct organisms. This method is commonly applied to fossil hominin hand bones to assess their abilities to participate in Paleolithic stone tool behaviors. Little is known, however, about how or even whether muscle anatomy and activity regimes influence the morphologies of their entheses, especially in the hand. Using the opponens muscles from a sample of modern humans, we tested the hypothesis that aspects of hand muscle architecture that are known to be influenced by behavior correlate with the size and shape of their associated entheses. Results show no consistent relationships between these behaviorally-influenced aspects of muscle architecture and entheseal morphology. Consequently, it is likely premature to infer patterns of behavior, such as stone tool making in fossil hominins, from these same entheses.

  5. Short-term high fat-feeding results in morphological and metabolic adaptations in the skeletal muscle of C57BL/6J mice

    NARCIS (Netherlands)

    Wilde, de J.; Mohren, R.; Berg, van den S.; Boekschoten, M.V.; Willems van Dijk, K.; Groot, de P.J.; Müller, M.R.; Mariman, E.; Smit, E.

    2008-01-01

    The prevalence of the metabolic syndrome (MS) is rapidly increasing all over the world. Consequently, there is an urgent need for more effective intervention strategies. Both animal and human studies indicate that lipid oversupply to skeletal muscle can result in insulin resistance which is one of

  6. In vivo passive mechanical behaviour of muscle fascicles and tendons in human gastrocnemius muscle-tendon units.

    Science.gov (United States)

    Herbert, Robert D; Clarke, Jillian; Kwah, Li Khim; Diong, Joanna; Martin, Josh; Clarke, Elizabeth C; Bilston, Lynne E; Gandevia, Simon C

    2011-11-01

    Ultrasound imaging was used to measure the length of muscle fascicles in human gastrocnemius muscles while the muscle was passively lengthened and shortened by moving the ankle. In some subjects the muscle belly 'buckled' at short lengths. When the gastrocnemius muscle-tendon unit was passively lengthened from its shortest in vivo length by dorsiflexing the ankle, increases in muscle-tendon length were not initially accompanied by increases in muscle fascicle lengths (fascicle length remained constant), indicating muscle fascicles were slack at short muscle-tendon lengths. The muscle-tendon length at which slack is taken up differs among fascicles: some fascicles begin to lengthen at very short muscle-tendon lengths whereas other fascicles remain slack over a large range of muscle-tendon lengths. This suggests muscle fascicles are progressively 'recruited' and contribute sequentially to muscle-tendon stiffness during passive lengthening of the muscle-tendon unit. Even above their slack lengths muscle fascicles contribute only a small part (tendon length. The contribution of muscle fascicles to muscle-tendon length increases with muscle length. The novelty of this work is that it reveals a previously unrecognised phenomenon (buckling at short lengths), posits a new mechanism of passive mechanical properties of muscle (recruitment of muscle fascicles), and confirms with high-resolution measurements that the passive compliance of human gastrocnemius muscle-tendon units is due largely to the tendon. It would be interesting to investigate if adaptations of passive properties of muscles are associated with changes in the distribution of muscle lengths at which fascicles fall slack.

  7. Possible mechanism for changes in glycogen metabolism in unloaded soleus muscle

    Science.gov (United States)

    Henriksen, E. J.; Tischler, M. E.

    1985-01-01

    Carbohydrate metabolism has been shown to be affected in a number of ways by different models of hypokinesia. In vivo glycogen levels in the soleus muscle are known to be increased by short-term denervation and harness suspension. In addition, exposure to 7 days of hypogravity also caused a dramatic increase in glycogen concentration in this muscle. The biochemical alterations caused by unloading that may bring about these increases in glycogen storage in the soleus were sought.

  8. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome

    OpenAIRE

    Petersen, Kitt Falk; Dufour, Sylvie; Savage, David B; Bilz, Stefan; Solomon, Gina; Yonemitsu, Shin; Cline, Gary W.; Befroy, Douglas; Zemany, Laura; Barbara B. Kahn; Papademetris, Xenophon; Rothman, Douglas L.; Shulman, Gerald I.

    2007-01-01

    We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by ≈60% in young, lean, insulin-resistant subjects compared with a similar cohort of age–weight–body mass index–activity-matched, insulin-sensitive, control subject...

  9. Emotions alter muscle proprioceptive coding of movements in humans.

    Science.gov (United States)

    Ackerley, Rochelle; Aimonetti, Jean-Marc; Ribot-Ciscar, Edith

    2017-08-16

    Emotions can evoke strong reactions that have profound influences, from gross changes in our internal environment to small fluctuations in facial muscles, and reveal our feelings overtly. Muscles contain proprioceptive afferents, informing us about our movements and regulating motor activities. Their firing reflects changes in muscle length, yet their sensitivity can be modified by the fusimotor system, as found in animals. In humans, the sensitivity of muscle afferents is modulated by cognitive processes, such as attention; however, it is unknown if emotional processes can modulate muscle feedback. Presently, we explored whether muscle afferent sensitivity adapts to the emotional situation. We recorded from single muscle afferents in the leg, using microneurography, and moved the ankle joint of participants, while they listened to evocative classical music to induce sad, neutral, or happy emotions, or sat passively (no music). We further monitored their physiological responses using skin conductance, heart rate, and electromyography measures. We found that muscle afferent firing was modified by the emotional context, especially for sad emotions, where the muscle spindle dynamic response increased. We suggest that this allows us to prime movements, where the emotional state prepares the body for consequent behaviour-appropriate reactions.

  10. Denervated muscles in humans: limitations and problems of currently used functional electrical stimulation training protocols.

    Science.gov (United States)

    Kern, Helmut; Hofer, Christian; Mödlin, Michaela; Forstner, Claudia; Raschka-Högler, Doris; Mayr, Winfried; Stöhr, Hans

    2002-03-01

    Prior clinical work showed that electrical stimulation therapy with exponential current is able to slow down atrophy and maintain the muscle during nonpermanent flaccid paralysis. However, exponential currents are not sufficient for long-term therapy of denervated degenerated muscles (DDMs). We initiated a European research project investigating the rehabilitation strategies in humans, but also studying the underlying basic scientific knowledge of muscle regeneration from satellite cells or myoblast activity in animal experiments. In our prior study, we were able to show that high-intensity stimulation of DDMs is possible. At the beginning of training, only single muscle twitches can be elicited by biphasic pulses with durations of 120-150 ms. Later, tetanic contraction of the muscle with special stimulation parameters (pulse duration of 30-50 ms, stimulation frequency of 16-25 Hz, pulse amplitudes of up to 250 mA) can improve the structural and metabolic state of the DDMs. Because there are no nerve endings for conduction of stimuli, large-size, anatomically shaped electrodes are used. This ensures an even contraction of the whole muscle. Contrary to the current clinical knowledge, we were able to stimulate and train denervated muscle 15-20 years after denervation. The estimated amount of muscle fibers that have to be restored is about 2-4 million fibers in each m. quadriceps. To rebuild such a large number of muscle fibers takes up to 3-4 years. Despite constant stimulation parameters and training protocols, there is a high variation in the developed contraction force and fatigue resistance of the muscle during the first years of functional electrical stimulation.

  11. Acclimation temperature affects the metabolic response of amphibian skeletal muscle to insulin.

    Science.gov (United States)

    Petersen, Ann M; Gleeson, Todd T

    2011-09-01

    Frog skeletal muscle mainly utilizes the substrates glucose and lactate for energy metabolism. The goal of this study was to determine the effect of insulin on the uptake and metabolic fate of lactate and glucose at rest in skeletal muscle of the American bullfrog, Lithobates catesbeiana, under varying temperature regimens. We hypothesize that lactate and glucose metabolic pathways will respond differently to the presence of insulin in cold versus warm acclimated frog tissues, suggesting an interaction between temperature and metabolism under varying environmental conditions. We employed radiolabeled tracer techniques to measure in vitro uptake, oxidation, and incorporation of glucose and lactate into glycogen by isolated muscles from bullfrogs acclimated to 5 °C (cold) or 25 °C (warm). Isolated bundles from Sartorius muscles were incubated at 5 °C, 15 °C, or 25 °C, and in the presence and absence of 0.05 IU/mL bovine insulin. Insulin treatment in the warm acclimated and incubated frogs resulted in an increase in glucose incorporation into glycogen, and an increase in intracellular [glucose] of 0.5 μmol/g (Pglycogen was reduced (Pglycogen synthesis, and a reduction in free intracellular glucose levels (Pmetabolism was attenuated or even reversed. Therefore, a significant interaction between insulin and acclimation condition in controlling skeletal muscle metabolism appears to exist. Our findings further suggest that one of insulin's actions in frog muscle is to increase glucose incorporation into glycogen, and to reduce reliance on lactate as the primary metabolic fuel. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

    Science.gov (United States)

    Sunitha, Balaraju; Gayathri, Narayanappa; Kumar, Manish; Keshava Prasad, Thottethodi Subrahmanya; Nalini, Atchayaram; Padmanabhan, Balasundaram; Srinivas Bharath, Muchukunte Mukunda

    2016-07-01

    Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies

  13. Underestimated contribution of skeletal muscle in ornithine metabolism during mouse postnatal development.

    Science.gov (United States)

    Ladeuix, Benjamin; Duchamp, Claude; Levillain, Olivier

    2014-01-01

    Ornithine aminotransferase (L-ornithine 2-oxoacid aminotransferase, OAT) is widely expressed in organs, but studies in mice have focused primarily on the intestine, kidney and liver because of the high OAT-specific activity in these tissues. This study aimed to investigate OAT activity in adult mouse tissues to assess the potential contribution to ornithine metabolism and to determine OAT control during postnatal development. OAT activity was widely distributed in mouse tissues. Sexual dimorphism was observed for most tissues in adults, with greater activity in females than in males. The contribution of skeletal muscles to total OAT activity (34% in males and 27% in females) was the greatest (50%) of the investigated tissues in pre-weaned mice and was similar to that of the liver in adults. OAT activity was found to be regulated in a tissue-specific manner during postnatal development in parallel with large changes in the plasma testosterone and corticosterone levels. After weaning, OAT activity markedly increased in the liver but dropped in the skeletal muscle and adipose tissue. Anticipating weaning for 3 days led to an earlier reduction of OAT activity in skeletal muscles. Orchidectomy in adults decreased OAT activity in the liver but increased it in skeletal muscle and adipose tissue. We concluded that the contribution of skeletal muscle to mouse ornithine metabolism may have been underestimated. The regulation of OAT in skeletal muscles differs from that in the liver. The present findings suggest important and tissue-specific metabolic roles for OAT during postnatal development in mice.

  14. Glucose metabolism and metabolic flexibility in cultured skeletal muscle cells is related to exercise status in young male subjects

    DEFF Research Database (Denmark)

    Lund, Jenny; S Tangen, Daniel; Wiig, Håvard

    2017-01-01

    deoxyglucose accumulation and fractional glucose oxidation (glucose oxidation relative to glucose uptake), and were also more sensitive to the suppressive action of acutely added oleic acid to the cells. Despite lack of correlation of fibre types between skeletal muscle biopsies and cultured cells, myotubes......We hypothesised that skeletal muscles of healthy young people have a large variation in oxidative capacity and fibre-type composition, and aimed therefore to investigate glucose metabolism in biopsies and myotubes isolated from musculus vastus lateralis from healthy males with varying degrees...

  15. Metabolic and muscle damage profiles of concentric versus repeated eccentric cycling.

    Science.gov (United States)

    Peñailillo, Luis; Blazevich, Anthony; Numazawa, Hideo; Nosaka, Kazunori

    2013-09-01

    Eccentric cycling is an exercise modality that could elicit multiple health benefits with low metabolic cost, but unaccustomed performance results in significant muscle damage. It is not known whether muscle damage is attenuated when eccentric cycling is repeated; thus, this study compared metabolic and muscle damage responses to concentric (CONC) and two consecutive eccentric (ECC1 and ECC2) cycling bouts. Ten men (28 ± 8 yr) performed each cycling bout for 30 min at 60% of the maximal concentric power output at 60 rpm, with 2 wk between bouts. HR, oxygen consumption (V˙O2), blood lactate (BLa), RPE, and muscle activity (EMG) data were collected during cycling. Maximal voluntary isometric knee extensor (MVC) strength, squat (SJ), countermovement jump (CMJ) height, muscle soreness indicators, and plasma creatine kinase (CK) activity were measured before, immediately after, and 1-4 d after exercise. Average HR, V˙O2, BLa, and RPE were lower (P < 0.05) during ECC1 than CONC, and EMG amplitude was also lower during ECC1 than CONC. Decreases in MVC, CMJ, and SJ and the increase in muscle soreness were greater (P x0003C; 0.05) after ECC1 than CONC. Increases in creatine kinase were minimal after all bouts. When comparing ECC1 and ECC2, HR and BLa were lower (P < 0.05) during ECC2 than ECC1, and decreases in MVC, CMJ, and SJ and the increase in muscle soreness were greater (P < 0.05) after ECC1 than ECC2. After ECC2, MVC, CMJ, and SJ did not change and no muscle soreness was developed. Eccentric cycling was less metabolically demanding than concentric cycling, and HR and BLa were further reduced during ECC2. Muscle damage is minimal after ECC2 and should not influence the choice to undertake eccentric cycling training.

  16. Muscle metabolism changes with age and maturation: How do they relate to youth sport performance?

    Science.gov (United States)

    Armstrong, Neil; Barker, Alan R; McManus, Alison M

    2015-07-01

    To provide an evidence-based review of muscle metabolism changes with sex-, age- and maturation with reference to the development of youth sport performance. A narrative review of data from both invasive and non-invasive studies, from 1970 to 2015, founded on personal databases supported with computer searches of PubMed and Google Scholar. Youth sport performance is underpinned by sex-, age- and maturation-related changes in muscle metabolism. Investigations of muscle size, structure and metabolism; substrate utilisation; pulmonary oxygen uptake kinetics; muscle phosphocreatine kinetics; peak anaerobic and aerobic performance; and fatigue resistance; determined using a range of conventional and emerging techniques present a consistent picture. Age-related changes have been consistently documented but specific and independent maturation-related effects on muscle metabolism during exercise have proved elusive to establish. Children are better equipped for exercise supported primarily by oxidative metabolism than by anaerobic metabolism. Sexual dimorphism is apparent in several physiological variables underpinning youth sport performance. As young people mature there is a progressive but asynchronous transition into an adult metabolic profile. The application of recent developments in technology to the laboratory study of the exercising child and adolescent has both supplemented existing knowledge and provided novel insights into developmental exercise physiology. A sound foundation of laboratory-based knowledge has been established but the lack of rigorously designed child-specific and sport-specific testing environments has clouded the interpretation of the data in real life situations. The primary challenge remains the translation of laboratory research into the optimisation of youth sports participation and performance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  17. Deletion of Kinin B2 Receptor Alters Muscle Metabolism and Exercise Performance.

    Directory of Open Access Journals (Sweden)

    Felipe C G Reis

    Full Text Available Metabolic syndrome is a cluster of metabolic risk factors such as obesity, diabetes and cardiovascular diseases. Mitochondria is the main site of ATP production and its dysfunction leads to decreased oxidative phosphorylation, resulting in lipid accumulation and insulin resistance. Our group has demonstrated that kinins can modulate glucose and lipid metabolism as well as skeletal muscle mass. By using B2 receptor knockout mice (B2R-/- we investigated whether kinin action affects weight gain and physical performance of the animals. Our results show that B2R-/- mice are resistant to high fat diet-induced obesity, have higher glucose tolerance as well as increased mitochondrial mass. These features are accompanied by higher energy expenditure and a lower feed efficiency associated with an increase in the proportion of type I fibers and intermediary fibers characterized by higher mitochondrial content and increased expression of genes related to oxidative metabolism. Additionally, the increased percentage of oxidative skeletal muscle fibers and mitochondrial apparatus in B2R-/- mice is coupled with a higher aerobic exercise performance. Taken together, our data give support to the involvement of kinins in skeletal muscle fiber type distribution and muscle metabolism, which ultimately protects against fat-induced obesity and improves aerobic exercise performance.

  18. Muscle carnitine availability plays a central role in regulating fuel metabolism in the rodent.

    Science.gov (United States)

    Porter, Craig; Constantin-Teodosiu, Dumitru; Constantin, Despina; Leighton, Brendan; Poucher, Simon M; Greenhaff, Paul L

    2017-09-01

    Meldonium inhibits endogenous carnitine synthesis and tissue uptake, and accelerates urinary carnitine excretion, although the impact of meldonium-mediated muscle carnitine depletion on whole-body fuel selection, and muscle fuel metabolism and its molecular regulation is under-investigated. Ten days of oral meldonium administration did not impact on food or fluid intake, physical activity levels or body weight gain in the rat, whereas it depleted muscle carnitine content (all moieties), increased whole-body carbohydrate oxidation and muscle and liver glycogen utilization, and reduced whole-body fat oxidation. Meldonium reduced carnitine transporter protein expression across muscles of different contractile and metabolic phenotypes. A TaqMan PCR low-density array card approach revealed the abundance of 189 mRNAs regulating fuel selection was altered in soleus muscle by meldonium, highlighting the modulation of discrete cellular functions and metabolic pathways. These novel findings strongly support the premise that muscle carnitine availability is a primary regulator of fuel selection in vivo. The body carnitine pool is primarily confined to skeletal muscle, where it regulates carbohydrate (CHO) and fat usage. Meldonium (3-(2,2,2-trimethylhydrazinium)-propionate) inhibits carnitine synthesis and tissue uptake, although the impact of carnitine depletion on whole-body fuel selection, muscle fuel metabolism and its molecular regulation is under-investigated. Male lean Zucker rats received water (control, n = 8) or meldonium-supplemented water (meldonium, n = 8) for 10 days [1.6 g kg -1 body mass (BM) day -1 days 1-2, 0.8 g kg -1  BM day -1 thereafter]. From days 7-10, animals were housed in indirect calorimetry chambers after which soleus muscle and liver were harvested. Food and fluid intake, weight gain and physical activity levels were similar between groups from days 7 to 10. Compared to control, meldonium depleted muscle total carnitine (P

  19. Acute exercise remodels promoter methylation in human skeletal muscle

    DEFF Research Database (Denmark)

    Barrès, Romain; Yan, Jie; Egan, Brendan

    2012-01-01

    DNA methylation is a covalent biochemical modification controlling chromatin structure and gene expression. Exercise elicits gene expression changes that trigger structural and metabolic adaptations in skeletal muscle. We determined whether DNA methylation plays a role in exercise-induced gene...... methylation of PGC-1a, PDK4, and PPAR-d was markedly decreased in mouse soleus muscles 45 min after ex vivo contraction. In L6 myotubes, caffeine exposure induced gene hypomethylation in parallel with an increase in the respective mRNA content. Collectively, our results provide evidence that acute gene...

  20. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

    Science.gov (United States)

    Risson, Valérie; Mazelin, Laetitia; Roceri, Mila; Sanchez, Hervé; Moncollin, Vincent; Corneloup, Claudine; Richard-Bulteau, Hélène; Vignaud, Alban; Baas, Dominique; Defour, Aurélia; Freyssenet, Damien; Tanti, Jean-François; Le-Marchand-Brustel, Yannick; Ferrier, Bernard; Conjard-Duplany, Agnès; Romanino, Klaas; Bauché, Stéphanie; Hantaï, Daniel; Mueller, Matthias; Kozma, Sara C.; Thomas, George; Rüegg, Markus A.; Ferry, Arnaud; Pende, Mario; Bigard, Xavier; Koulmann, Nathalie

    2009-01-01

    Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent. PMID:20008564

  1. Molecular aging and rejuvenation of human muscle stem cells

    OpenAIRE

    Carlson, Morgan E; Suetta, Charlotte; Conboy, Michael J.; Aagaard, Per; Mackey, Abigail; Kjaer, Michael; Conboy, Irina

    2009-01-01

    Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response ...

  2. Exercise training dose differentially alters muscle and heart capillary density and metabolic functions in an obese rat with metabolic syndrome.

    Science.gov (United States)

    Machado, Marcus Vinicius; Vieira, Aline Bomfim; da Conceição, Fabiana Gomes; Nascimento, Alessandro Rodrigues; da Nóbrega, Antonio Claudio Lucas; Tibirica, Eduardo

    2017-12-01

    What is the central question of this study? Regular exercise is recommended as a non-pharmacological approach for the prevention and treatment of metabolic syndrome. However, the impact of different combinations of intensity, duration and frequency of exercise on metabolic syndrome and microvascular density has not been reported. What is the main finding and its importance? We provide evidence on the impact of aerobic exercise dose on metabolic and microvascular alterations in an experimental model of metabolic syndrome induced by high-fat diet. We found that the exercise frequency and duration were the main factors affecting anthropometric and metabolic parameters and microvascular density in the skeletal muscle. Exercise intensity was related only to microvascular density in the heart. We evaluated the effect of the frequency, duration and intensity of exercise training on metabolic parameters and structural capillary density in obese rats with metabolic syndrome. Wistar-Kyoto rats were fed either a standard commercial diet (CON) or a high-fat diet (HFD). Animals that received the HFD were randomly separated into either a sedentary (SED) group or eight different exercise groups that varied according to the frequency, duration and intensity of training. After 12 weeks of aerobic exercise training, the body composition, aerobic capacity, haemodynamic variables, metabolic parameters and capillary density in the heart and skeletal muscle were evaluated. All the exercise training groups showed reduced resting systolic blood pressure and heart rate and normalized fasting glucose. The minimal amount of exercise (90 min per week) produced little effect on metabolic syndrome parameters. A moderate amount of exercise (150 min per week) was required to reduce body weight and improve capillary density. However, only the high amount of exercise (300 min per week) significantly reduced the amount of body fat depots. The three-way ANOVA showed a main effect of exercise

  3. Erythropoietin treatment enhances muscle mitochondrial capacity in humans

    DEFF Research Database (Denmark)

    Plenge, Ulla; Belhage, Bo; Guadalupe-Grau, Amelia

    2012-01-01

    Erythropoietin (Epo) treatment has been shown to induce mitochondrial biogenesis in cardiac muscle along with enhanced mitochondrial capacity in mice. We hypothesized that recombinant human Epo (rhEpo) treatment enhances skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity...... in humans. In six healthy volunteers rhEpo was administered by sub-cutaneous injection over 8 weeks with oral iron (100 mg) supplementation taken daily. Mitochondrial OXPHOS was quantified by high-resolution respirometry in saponin-permeabilized muscle fibers obtained from biopsies of the vastus lateralis....... rhEpo treatment increased OXPHOS (from 92 ± 5 to 113 ± 7 pmol·s(-1)·mg(-1)) and ETS (107 ± 4 to 143 ± 14 pmol·s(-1)·mg(-1), p muscle....

  4. Functional and molecular outcomes of the human masticatory muscles.

    Science.gov (United States)

    Isola, G; Anastasi, G P; Matarese, G; Williams, R C; Cutroneo, G; Bracco, P; Piancino, M G

    2017-11-20

    The masticatory muscles achieve a broad range of different activities such as chewing, sucking, swallowing, and speech. In order to accomplish these duties, masticatory muscles have a unique and heterogeneous structure and fiber composition, enabling them to produce their strength and contraction speed largely dependent on their motor units and myosin proteins that can change in response to genetic and environmental factors. Human masticatory muscles express unique myosin isoforms, including a combination of thick fibers, expressing myosin light chains (MyLC) and myosin class I and II heavy chains (MyHC) -IIA, -IIX, α-cardiac, embryonic and neonatal and thin fibers, respectively. In this review, we discuss the current knowledge regarding the importance of fiber-type diversity in masticatory muscles versus supra- and infrahyoid muscles, and versus limb and trunk muscles. We also highlight new information regarding the adaptive response and specific genetic variations of muscle fibers on the functional significance of the masticatory muscles, which influences craniofacial characteristics, malocclusions, or asymmetry. These findings may offer future possibilities for the prevention of craniofacial growth disturbances. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.

  5. Corticospinal contribution to arm muscle activity during human walking

    DEFF Research Database (Denmark)

    Barthélemy, Dorothy; Nielsen, Jens Bo

    2010-01-01

    When we walk, our arm muscles show rhythmic activity suggesting that the central nervous system contributes to the swing of the arms. The purpose of the present study was to investigate whether corticospinal drive plays a role in the control of arm muscle activity during human walking. Motor evoked...... inhibitory interneurones, the suppression is in all likelihood caused by removal of a corticospinal contribution to the ongoing EMG activity. The data thus suggest that the motor cortex makes an active contribution, through the corticospinal tract, to the ongoing EMG activity in arm muscles during walking....

  6. Pharmacomechanical coupling in smooth muscle may involve phosphatidylinositol metabolism.

    OpenAIRE

    Baron, C B; Cunningham, M; Strauss, J F; Coburn, R F

    1984-01-01

    Cholinergic contraction of canine trachealis muscle, a contraction that primarily utilizes membrane potential-independent mechanisms for activating contractile proteins (pharmacomechanical coupling), is associated with a decline in the phosphatidylinositol pool, an increase in the phosphatidic acid and diacylglycerol pools, and an increased incorporation of 32PO4 into phosphatidylinositol. We found that these changes occur during development of the contraction and during maintenance of tensio...

  7. Metabolic and transcriptional changes in cultured muscle stem cells from low birth weight subjects

    DEFF Research Database (Denmark)

    Hansen, Ninna S; Hjort, Line; Broholm, Christa

    2016-01-01

    CONTEXT/OBJECTIVE: Developmental programming of human muscle stem cells could in part explain why individuals born with low birth weight (LBW) have an increased risk of developing type 2 diabetes (T2D) later in life. We hypothesized that immature muscle stem cell functions including abnormal...

  8. Myosin Heavy Chain Composition of the Human Genioglossus Muscle

    Science.gov (United States)

    Daugherty, Megan; Luo, Qingwei; Sokoloff, Alan J.

    2012-01-01

    Background: The human tongue muscle genioglossus (GG) is active in speech, swallowing, respiration, and oral transport, behaviors encompassing a wide range of tongue shapes and movement speeds. Studies demonstrate substantial diversity in patterns of human GG motor unit activation, but whether this is accompanied by complex expression of muscle…

  9. Doxorubicin induces inflammatory modulation and metabolic dysregulation in diabetic skeletal muscle

    Directory of Open Access Journals (Sweden)

    Rashmi Supriya

    2016-07-01

    Full Text Available Anti-cancer agent doxorubicin (DOX has been demonstrated to worsen insulin signaling, engender muscle atrophy, trigger pro-inflammation, and induce a shift to anaerobic glycolytic metabolism in skeletal muscle. The myotoxicity of DOX in diabetic skeletal muscle remains largely unclear. This study examined the effects of DOX on insulin signaling, muscle atrophy, pro-/anti-inflammatory microenvironment, and glycolysis metabolic regulation in skeletal muscle of db/db diabetic and db/+ non-diabetic mice. Non-diabetic db/+ mice and diabetic db/db mice were randomly assigned to the following groups: db/+CON, db/+DOX, db/dbCON, and db/dbDOX. Mice in db/+DOX and db/dbDOX groups were intraperitoneally injected with DOX at a dose of 15 mg per kg body weight whereas mice in db/+CON and db/dbCON groups were injected with the same volume of saline instead of DOX. Gastrocnemius was immediately harvested, weighed, washed with cold phosphate buffered saline, frozen in liquid nitrogen, and stored at -80 ºC for later analysis. The effects of DOX on diabetic muscle were neither seen in insulin signaling markers (Glut4, pIRS1Ser636/639, and pAktSer473 nor muscle atrophy markers (muscle mass, MuRF1 and MAFbx. However, DOX exposure resulted in enhancement of pro-inflammatory favoring microenvironment (as indicated by TNF-α, HIFα and pNFκBp65 accompanied by diminution of anti-inflammatory favoring microenvironment (as indicated by IL15, PGC1α and pAMPKβ1Ser108. Metabolism of diabetic muscle was shifted to anaerobic glycolysis after DOX exposure as demonstrated by our analyses of PDK4, LDH and pACCSer79. Our results demonstrated that there might be a link between inflammatory modulation and the dysregulation of aerobic glycolytic metabolism in DOX-injured diabetic skeletal muscle. These findings help to understand the pathogenesis of DOX-induced myotoxicity in diabetic muscle.

  10. A community-driven global reconstruction of human metabolism

    NARCIS (Netherlands)

    Thiele, Ines; Swainston, Neil; Fleming, Ronan M. T.; Hoppe, Andreas; Sahoo, Swagatika; Aurich, Maike K.; Haraldsdottir, Hulda; Mo, Monica L.; Rolfsson, Ottar; Stobbe, Miranda D.; Thorleifsson, Stefan G.; Agren, Rasmus; Bölling, Christian; Bordel, Sergio; Chavali, Arvind K.; Dobson, Paul; Dunn, Warwick B.; Endler, Lukas; Hala, David; Hucka, Michael; Hull, Duncan; Jameson, Daniel; Jamshidi, Neema; Jonsson, Jon J.; Juty, Nick; Keating, Sarah; Nookaew, Intawat; Le Novère, Nicolas; Malys, Naglis; Mazein, Alexander; Papin, Jason A.; Price, Nathan D.; Selkov, Evgeni; Sigurdsson, Martin I.; Simeonidis, Evangelos; Sonnenschein, Nikolaus; Smallbone, Kieran; Sorokin, Anatoly; van Beek, Johannes H. G. M.; Weichart, Dieter; Goryanin, Igor; Nielsen, Jens; Westerhoff, Hans V.; Kell, Douglas B.; Mendes, Pedro; Palsson, Bernhard Ø

    2013-01-01

    Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven, consensus 'metabolic reconstruction', which is the most comprehensive representation of human metabolism that is applicable to computational

  11. Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates

    DEFF Research Database (Denmark)

    Hoffman, Nolan J; Parker, Benjamin L; Chaudhuri, Rima

    2015-01-01

    Exercise is essential in regulating energy metabolism and whole-body insulin sensitivity. To explore the exercise signaling network, we undertook a global analysis of protein phosphorylation in human skeletal muscle biopsies from untrained healthy males before and after a single high...

  12. The Human Tongue Slows Down to Speak: Muscle Fibers of the Human Tongue

    Science.gov (United States)

    SANDERS, IRA; MU, LIANCAI; AMIRALI, ASIF; SU, HUNGXI; SOBOTKA, STANISLAW

    2013-01-01

    Little is known about the specializations of human tongue muscles. In this study, myofibrillar adenosine triphosphatase (mATPase) histochemical staining was used to study the percentage and distribution of slow twitch muscle fibers (slow MFs) within tongue muscles of 4 neurologically normal human adults and specimens from a 2 year old human, a newborn human, an adult with idiopathic Parkinson’s disease (IPD), and a macaque monkey. The average percentage of slow MFs in adult and the 2 year old muscle specimens was 54%, the IPD was 45%, while the neonatal human (32%) and macaque monkey (28%) had markedly fewer slow MFs. In contrast the tongue muscles of the rat and cat have been reported to have no slow MFs. There was a marked spatial gradient in the distribution of slow MFs with the highest percentages found medially and posterially. Normal adult tongue muscles were found to have a variety of uniquely specialized features including MF type grouping (usually found in neuromuscular disorders), large amounts of loose connective tissue, and short branching MFs. In summary, normal adult human tongue muscles have by far the highest proportion of slow MFs of any mammalian tongue studied to date. Moreover, adult human tongue muscles have multiple unique anatomic features. As the tongue shape changes that are seen during speech articulation are unique to humans we hypothesize that the large proportion of slow MFs and the anatomical specializations observed in the adult human tongue have evolved to perform these movements. PMID:23929762

  13. Skeletal muscle metabolism after stroke: A comparative study using treadmill and overground walking test

    Directory of Open Access Journals (Sweden)

    Ana Paula C. Loureiro

    2017-06-01

    Full Text Available Objective: The primary aim of this study was to investigate muscle metabolism in stroke survivors through measurements of the respiratory exchange ratio and rates of fat and carbohydrate oxidation in relation to total energy expenditure at preferred walking speed during treadmill and overground walking. The secondary objective was to investigate whether the energy source used during walking influences the daily physical activity pattern and fatigue of post-stroke individuals. Methods: The sample comprised 28 stroke participants and 10 non-disabled, healthy controls. Measurements of oxygen consumption and carbon dioxide production were recorded. Participants wore a uniaxial accelerometer (activPAL™ over 4 days as an estimate of daily physical activity. Measurements of Human Activity Profile and Neurological Fatigue Index for stroke were documented. Results: Carbohydrate oxidation accounted for the majority of fuel oxidation at preferred walking speed in the stroke group (55.86% vs 47.29% during tread-mill walking and 66.13% vs 50.15% during overground walking. Stroke patients who had higher levels of carbohydrate oxidation reached a lower score in the Human Activity Profile survey, had fewer steps screened by activPAL data (4,422 vs 6,692 steps/day and higher fatigue index. Conclusion: Carbohydrate oxidation accounted for the majority of fuel oxidation at the preferred walking speed in post-stroke individuals. The increased carbohydrate utilization recorded at preferred walking speed may have influenced the physical activity profile.

  14. Skeletal muscle metabolism after stroke: A comparative study using treadmill and overground walking test.

    Science.gov (United States)

    Loureiro, Ana Paula C; Langhammer, Birgitta; Gjøvaag, Terje; Ihle-Hansen, Hege; Guarita-Souza, Luiz César

    2017-07-07

    The primary aim of this study was to investigate muscle metabolism in stroke survivors through measurements of the respiratory exchange ratio and rates of fat and carbohydrate oxidation in relation to total energy expenditure at preferred walking speed during treadmill and overground walking. The secondary objective was to investigate whether the energy source used during walking influences the daily physical activity pattern and fatigue of post-stroke individuals. The sample comprised 28 stroke participants and 10 non-disabled, healthy controls. Measurements of oxygen consumption and carbon dioxide production were recorded. Participants wore a uniaxial accelerometer (activPAL™) over 4 days as an estimate of daily physical activity. Measurements of Human Activity Profile and Neurological Fatigue Index for stroke were documented. Carbohydrate oxidation accounted for the majority of fuel oxidation at preferred walking speed in the stroke group (55.86% vs 47.29% during tread-mill walking and 66.13% vs 50.15% during overground walking). Stroke patients who had higher levels of carbohydrate oxidation reached a lower score in the Human Activity Profile survey, had fewer steps screened by activPAL data (4,422 vs 6,692 steps/day) and higher fatigue index. Carbohydrate oxidation accounted for the majority of fuel oxidation at the preferred walking speed in post-stroke individuals. The increased carbohydrate utilization recorded at preferred walking speed may have influenced the physical activity profile.

  15. Peroxisomes are required for lipid metabolism and muscle function in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Joseph E Faust

    Full Text Available Peroxisomes are ubiquitous organelles that perform lipid and reactive oxygen species metabolism. Defects in peroxisome biogenesis cause peroxisome biogenesis disorders (PBDs. The most severe PBD, Zellweger syndrome, is characterized in part by neuronal dysfunction, craniofacial malformations, and low muscle tone (hypotonia. These devastating diseases lack effective therapies and the development of animal models may reveal new drug targets. We have generated Drosophila mutants with impaired peroxisome biogenesis by disrupting the early peroxin gene pex3, which participates in budding of pre-peroxisomes from the ER and peroxisomal membrane protein localization. pex3 deletion mutants lack detectible peroxisomes and die before or during pupariation. At earlier stages of development, larvae lacking Pex3 display reduced size and impaired lipid metabolism. Selective loss of peroxisomes in muscles impairs muscle function and results in flightless animals. Although, hypotonia in PBD patients is thought to be a secondary effect of neuronal dysfunction, our results suggest that peroxisome loss directly affects muscle physiology, possibly by disrupting energy metabolism. Understanding the role of peroxisomes in Drosophila physiology, specifically in muscle cells may reveal novel aspects of PBD etiology.

  16. Peroxisomes are required for lipid metabolism and muscle function in Drosophila melanogaster.

    Science.gov (United States)

    Faust, Joseph E; Manisundaram, Arvind; Ivanova, Pavlina T; Milne, Stephen B; Summerville, James B; Brown, H Alex; Wangler, Michael; Stern, Michael; McNew, James A

    2014-01-01

    Peroxisomes are ubiquitous organelles that perform lipid and reactive oxygen species metabolism. Defects in peroxisome biogenesis cause peroxisome biogenesis disorders (PBDs). The most severe PBD, Zellweger syndrome, is characterized in part by neuronal dysfunction, craniofacial malformations, and low muscle tone (hypotonia). These devastating diseases lack effective therapies and the development of animal models may reveal new drug targets. We have generated Drosophila mutants with impaired peroxisome biogenesis by disrupting the early peroxin gene pex3, which participates in budding of pre-peroxisomes from the ER and peroxisomal membrane protein localization. pex3 deletion mutants lack detectible peroxisomes and die before or during pupariation. At earlier stages of development, larvae lacking Pex3 display reduced size and impaired lipid metabolism. Selective loss of peroxisomes in muscles impairs muscle function and results in flightless animals. Although, hypotonia in PBD patients is thought to be a secondary effect of neuronal dysfunction, our results suggest that peroxisome loss directly affects muscle physiology, possibly by disrupting energy metabolism. Understanding the role of peroxisomes in Drosophila physiology, specifically in muscle cells may reveal novel aspects of PBD etiology.

  17. Developmental Programming in Response to Intrauterine Growth Restriction Impairs Myoblast Function and Skeletal Muscle Metabolism

    Directory of Open Access Journals (Sweden)

    D. T. Yates

    2012-01-01

    Full Text Available Fetal adaptations to placental insufficiency alter postnatal metabolic homeostasis in skeletal muscle by reducing glucose oxidation rates, impairing insulin action, and lowering the proportion of oxidative fibers. In animal models of intrauterine growth restriction (IUGR, skeletal muscle fibers have less myonuclei at birth. This means that myoblasts, the sole source for myonuclei accumulation in fibers, are compromised. Fetal hypoglycemia and hypoxemia are complications that result from placental insufficiency. Hypoxemia elevates circulating catecholamines, and chronic hypercatecholaminemia has been shown to reduce fetal muscle development and growth. We have found evidence for adaptations in adrenergic receptor expression profiles in myoblasts and skeletal muscle of IUGR sheep fetuses with placental insufficiency. The relationship of β-adrenergic receptors shifts in IUGR fetuses because Adrβ2 expression levels decline and Adrβ1 expression levels are unaffected in myofibers and increased in myoblasts. This adaptive response would suppress insulin signaling, myoblast incorporation, fiber hypertrophy, and glucose oxidation. Furthermore, this β-adrenergic receptor expression profile persists for at least the first month in IUGR lambs and lowers their fatty acid mobilization. Developmental programming of skeletal muscle adrenergic receptors partially explains metabolic and endocrine differences in IUGR offspring, and the impact on metabolism may result in differential nutrient utilization.

  18. Phthalate exposure changes the metabolic profile of cardiac muscle cells.

    Science.gov (United States)

    Posnack, Nikki Gillum; Swift, Luther M; Kay, Matthew W; Lee, Norman H; Sarvazyan, Narine

    2012-09-01

    Phthalates are common plasticizers present in medical-grade plastics and other everyday products. They can also act as endocrine-disrupting chemicals and have been linked to the rise in metabolic disorders. However, the effect of phthalates on cardiac metabolism remains largely unknown. We examined the effect of di(2-ethylhexyl)phthalate (DEHP) on the metabolic profile of cardiomyocytes because alterations in metabolic processes can lead to cell dysfunction. Neonatal rat cardiomyocytes were treated with DEHP at a concentration and duration comparable to clinical exposure (50-100 μg/mL, 72 hr). We assessed the effect of DEHP on gene expression using microarray analysis. Physiological responses were examined via fatty acid utilization, oxygen consumption, mitochondrial mass, and Western blot analysis. Exposure to DEHP led to up-regulation of genes associated with fatty acid transport, esterification, mitochondrial import, and β-oxidation. The functional outcome was an increase in myocyte fatty acid-substrate utilization, oxygen consumption, mitochondrial mass, PPARα (peroxisome proliferator-activated receptor α) protein expression, and extracellular acidosis. Treatment with a PPARα agonist (Wy-14643) only partially mimicked the effects observed in DEHP-treated cells. Data suggest that DEHP exposure results in metabolic remodeling of cardiomyocytes, whereby cardiac cells increase their dependence on fatty acids for energy production. This fuel switch may be regulated at both the gene expression and posttranscription levels. Our findings have important clinical implications because chronic dependence on fatty acids is associated with an accumulation in lipid intermediates, lactate, protons, and reactive oxygen species. This dependence can sensitize the heart to ischemic injury and ventricular dysfunction.

  19. Metabolic and physiologic characteristics of skeletal muscle determine its response to clenbuterol treatment.

    Science.gov (United States)

    Sundal, Santosh; Katoch, Surender S; Sharma, Sushma

    2006-06-01

    beta-Adrenoceptor agonists are reported to induce skeletal muscle hypertrophy and hence serve as valuable adjunct to the treatment of wasting disorders. In the present study, we attempted to find out whether metabolic and physiologic characteristics of fibres are important in determining skeletal muscle response to clenbuterol (an adrenergic receptor agonist) therapy, as proposed in the treatment of wasting disorders. The treatment of mice with clenbuterol (2 mg/kg body wt for 30 days) resulted in skeletal muscle hypertrophy, more common amongst fast-twitch glycolytic fibres/muscle, with increase in body mass and a parallel rise in muscle mass to body mass ratio. Measurement of fibre diameters in soleus (rich in slow-twitch oxidative fibres), ALD or anterior latissimus dorsi (with a predominance of fast-twitch glycolytic fibres) and gastrocnemius (a mixed-type of muscle) from clenbuterol-treated mice for 30 days revealed noticeable increase in the per cent population of narrow slow-twitch fibre and a corresponding decline in white-type or fast-twitch glycolytic fibres in gastrocnemius and ALD. As revealed by counting of muscle cells in soleus, narrow red fibres declined with corresponding increase in white-type glycolytic fibres population. A significant decline in the succinic dehydrogenase activity was observed, thereby suggesting abnormality in oxidative activity of skeletal muscles in response to clenbuterol therapy.

  20. Oxidation of urate in human skeletal muscle during exercise

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Tullson, P. C.; Richter, Erik

    1997-01-01

    exercise (p 3 min after exercise (p 2.6 mumol.liter-1 at rest and by 5 min.......084 +/- 0.016 mumol.g-1 w.w. (p exercise and then rapidly increased during recovery to reach the resting level within 3 min after exercise. The concentration of allantoin in the muscle increased from a resting value of 0.03 +/- 0.007 to 0.10 +/- 0.014 mumol.g-1 w.w. immediately after......The purpose of the present study was to investigate whether high metabolic stress to skeletal muscle, induced by intensive exercise, would lead to an oxidation of urate to allantoin in the exercised muscle. Seven healthy male subjects performed short term (4.39 +/- 0.04 [+/-SE] min) exhaustive...

  1. Control of Muscle Mitochondria by Insulin Entails Activation of Akt2-mtNOS Pathway: Implications for the Metabolic Syndrome

    Science.gov (United States)

    Finocchietto, Paola; Barreyro, Fernando; Holod, Silvia; Peralta, Jorge; Franco, María C.; Méndez, Carlos; Converso, Daniela P.; Estévez, Alvaro; Carreras, Maria C.; Poderoso, Juan J.

    2008-01-01

    Background In the metabolic syndrome with hyperinsulinemia, mitochondrial inhibition facilitates muscle fat and glycogen accumulation and accelerates its progression. In the last decade, nitric oxide (NO) emerged as a typical mitochondrial modulator by reversibly inhibiting citochrome oxidase and oxygen utilization. We wondered whether insulin-operated signaling pathways modulate mitochondrial respiration via NO, to alternatively release complete glucose oxidation to CO2 and H2O or to drive glucose storage to glycogen. Methodology/Principal Findings We illustrate here that NO produced by translocated nNOS (mtNOS) is the insulin-signaling molecule that controls mitochondrial oxygen utilization. We evoke a hyperinsulinemic-normoglycemic non-invasive clamp by subcutaneously injecting adult male rats with long-lasting human insulin glargine that remains stable in plasma by several hours. At a precise concentration, insulin increased phospho-Akt2 that translocates to mitochondria and determines in situ phosphorylation and substantial cooperative mtNOS activation (+4–8 fold, Pinsulin metabolic effects on gastrocnemius muscles by direct electroporation of siRNA nNOS or empty vector in the two legs of the same animal, confirmed that in the silenced muscles disrupted mtNOS allows higher oxygen uptake and complete (U-14C)-glucose utilization respect to normal mtNOS in the vector-treated ones (respectively 37±3 vs 10±1 µmolO2/h.g tissue and 13±1 vs 7.2±1 µmol 3H2O/h.g tissue, Pinsulin depresses mitochondrial respiration in skeletal muscle via NO which permits substrates to be deposited as macromolecules; at discrete hyperinsulinemia, persistent mtNOS activation could contribute to mitochondrial dysfunction with insulin resistance and obesity and therefore, to the progression of the metabolic syndrome. PMID:18335029

  2. Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle.

    Science.gov (United States)

    Sato, Koji; Iemitsu, Motoyuki; Aizawa, Katsuji; Ajisaka, Ryuichi

    2008-05-01

    Circulating dehydroepiandrosterone (DHEA) is converted to testosterone or estrogen in the target tissues. Recently, we demonstrated that skeletal muscles are capable of locally synthesizing circulating DHEA to testosterone and estrogen. Furthermore, testosterone is converted to 5alpha-dihydrotestosterone (DHT) by 5alpha-reductase and exerts biophysiological actions through binding to androgen receptors. However, it remains unclear whether skeletal muscle can synthesize DHT from testosterone and/or DHEA and whether these hormones affect glucose metabolism-related signaling pathway in skeletal muscles. We hypothesized that locally synthesized DHT from testosterone and/or DHEA activates glucose transporter-4 (GLUT-4)-regulating pathway in skeletal muscles. The aim of the present study was to clarify whether DHT is synthesized from testosterone and/or DHEA in cultured skeletal muscle cells and whether these hormones affect the GLUT-4-related signaling pathway in skeletal muscles. In the present study, the expression of 5alpha-reductase mRNA was detected in rat cultured skeletal muscle cells, and the addition of testosterone or DHEA increased intramuscular DHT concentrations. Addition of testosterone or DHEA increased GLUT-4 protein expression and its translocation. Furthermore, Akt and protein kinase C-zeta/lambda (PKC-zeta/lambda) phosphorylations, which are critical in GLUT-4-regulated signaling pathways, were enhanced by testosterone or DHEA addition. Testosterone- and DHEA-induced increases in both GLUT-4 expression and Akt and PKC-zeta/lambda phosphorylations were blocked by a DHT inhibitor. Finally, the activities of phosphofructokinase and hexokinase, main glycolytic enzymes, were enhanced by testosterone or DHEA addition. These findings suggest that skeletal muscle is capable of synthesizing DHT from testosterone, and that DHT activates the glucose metabolism-related signaling pathway in skeletal muscle cells.

  3. Muscle mitochondrial stress-induced metabolic adaptations do not require FGF21 action

    NARCIS (Netherlands)

    Schothorst, van Evert; Ost, Mario; Stelt, van der Inge; Klaus, Susanne; Keijer, Jaap

    2016-01-01

    Fibroblast growth factor 21 (FGF21) is a key metabolic regulator which was recently discovered as stress-induced myokine and common denominator of muscle mitochondrial disease. However, its precise function and pathophysiological relevance remains unknown. Here we demonstrate that white adipose

  4. Exercise improves fat metabolism in muscle but does not increase 24-h fat oxidation

    OpenAIRE

    Melanson, Edward L; Paul S MacLean; Hill, James O.

    2009-01-01

    Despite decades of research into the effects of exercise on fat metabolism, there is still no clear understanding of how exercise helps to regulate fat mass. Although exercise improves the capacity of muscle to oxidize fat, our studies suggest that moderate duration exercise (≤ 1 hr) has little impact on 24-h fat oxidation.

  5. Dietary fat influences the expression of contractile and metabolic genes in rat skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Wataru Mizunoya

    Full Text Available Dietary fat plays a major role in obesity, lipid metabolism, and cardiovascular diseases. To determine whether the intake of different types of dietary fats affect the muscle fiber types that govern the metabolic and contractile properties of the skeletal muscle, we fed male Wistar rats with a 15% fat diet derived from different fat sources. Diets composed of soybean oil (n-6 polyunsaturated fatty acids (PUFA-rich, fish oil (n-3 PUFA-rich, or lard (low in PUFAs were administered to the rats for 4 weeks. Myosin heavy chain (MyHC isoforms were used as biomarkers to delineate the skeletal muscle fiber types. Compared with soybean oil intake, fish oil intake showed significantly lower levels of the fast-type MyHC2B and higher levels of the intermediate-type MyHC2X composition in the extensor digitorum longus (EDL muscle, which is a fast-type dominant muscle. Concomitantly, MyHC2X mRNA levels in fish oil-fed rats were significantly higher than those observed in the soybean oil-fed rats. The MyHC isoform composition in the lard-fed rats was an intermediate between that of the fish oil and soybean oil-fed rats. Mitochondrial uncoupling protein 3, pyruvate dehydrogenase kinase 4, and porin mRNA showed significantly upregulated levels in the EDL of fish oil-fed rats compared to those observed in soybean oil-fed and lard-fed rats, implying an activation of oxidative metabolism. In contrast, no changes in the composition of MyHC isoforms was observed in the soleus muscle, which is a slow-type dominant muscle. Fatty acid composition in the serum and the muscle was significantly influenced by the type of dietary fat consumed. In conclusion, dietary fat affects the expression of genes related to the contractile and metabolic properties in the fast-type dominant skeletal muscle, where the activation of oxidative metabolism is more pronounced after fish oil intake than that after soybean oil intake.

  6. A new Caenorhabditis elegans model of human huntingtin 513 aggregation and toxicity in body wall muscles.

    Directory of Open Access Journals (Sweden)

    Amy L Lee

    Full Text Available Expanded polyglutamine repeats in different proteins are the known determinants of at least nine progressive neurodegenerative disorders whose symptoms include cognitive and motor impairment that worsen as patients age. One such disorder is Huntington's Disease (HD that is caused by a polyglutamine expansion in the human huntingtin protein (htt. The polyglutamine expansion destabilizes htt leading to protein misfolding, which in turn triggers neurodegeneration and the disruption of energy metabolism in muscle cells. However, the molecular mechanisms that underlie htt proteotoxicity have been somewhat elusive, and the muscle phenotypes have not been well studied. To generate tools to elucidate the basis for muscle dysfunction, we engineered Caenorhabditis elegans to express a disease-associated 513 amino acid fragment of human htt in body wall muscle cells. We show that this htt fragment aggregates in C. elegans in a polyglutamine length-dependent manner and is toxic. Toxicity manifests as motor impairment and a shortened lifespan. Compared to previous models, the data suggest that the protein context in which a polyglutamine tract is embedded alters aggregation propensity and toxicity, likely by affecting interactions with the muscle cell environment.

  7. Genetic and metabolic effects on skeletal muscle AMPK in young and older twins

    DEFF Research Database (Denmark)

    Mortensen, Brynjulf; Poulsen, Pernille; Wegner, Lise

    2009-01-01

    The protein complex AMP-activated protein kinase (AMPK) is believed to play an important role in the regulation of skeletal muscle glucose and lipid metabolism. Defects in the AMPK system might therefore be an important factor in the pathogenesis of type 2 diabetes. We aimed to identify genetic...... indicated that skeletal muscle AMPK mRNA and protein expression as well as activity were regulated by sex, age, obesity, and aerobic capacity. Comparison of intraclass correlations on AMPK measures from mono- and dizygotic twins suggested that skeletal muscle AMPK expression was under minor genetic...... genetic control but regulated by age and sex and associated with obesity and aerobic capacity. Furthermore, our results indicate a role for gamma3-containing AMPK complexes in down-regulation of insulin-stimulated non-oxidative glucose metabolism possibly through inhibition of glycogen synthase activity...

  8. Metabolic profile of dystrophic mdx mouse muscles analyzed with in vitro magnetic resonance spectroscopy (MRS).

    Science.gov (United States)

    Martins-Bach, Aurea B; Bloise, Antonio C; Vainzof, Mariz; Rahnamaye Rabbani, Said

    2012-10-01

    Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy characterized by progressive and irreversible degeneration of the muscles. The mdx mouse is the classical animal model for DMD, showing similar molecular and protein defects. The mdx mouse, however, does not show significant muscle weakness, and the diaphragm muscle is significantly more degenerated than skeletal muscles. In this work, (1)H magnetic resonance spectroscopy (MRS) was used to study the metabolic profile of quadriceps and diaphragm muscles from mdx and control mice. Using principal components analysis (PCA), the animals were separated into groups according to age and lineages. The classification was compared to histopathological analysis. Among the 24 metabolites identified from the nuclear MR spectra, only 19 were used by the PCA program for classification purposes. These can be important key biomarkers associated with the progression of degeneration in mdx muscles and with natural aging in control mice. Glutamate, glutamine, succinate, isoleucine, acetate, alanine and glycerol were increased in mdx samples as compared to control mice, in contrast to carnosine, taurine, glycine, methionine and creatine that were decreased. These results suggest that MRS associated with pattern recognition analysis can be a reliable tool to assess the degree of pathological and metabolic alterations in the dystrophic tissue, thereby affording the possibility of evaluation of beneficial effects of putative therapies. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Regulation of the skeletal muscle blood flow in humans

    DEFF Research Database (Denmark)

    Mortensen, Stefan; Saltin, Bengt

    2014-01-01

    hyperaemia whereas the role of ATP remains uncertain due to lack of specific purinergic receptor blockers for human use. The purpose of this review is to address the interaction between vasodilator systems and to discuss the multiple proposed roles of ATP in human skeletal muscle blood flow regulation......In humans, skeletal muscle blood flow is regulated by an interaction between several locally formed vasodilators including nitric oxide (NO) and prostaglandins. In plasma, ATP is a potent vasodilator that stimulates the formation of NO and prostaglandins and very importantly can offset local...... sympathetic vasoconstriction. ATP is released into plasma from erythrocytes and endothelial cells and the plasma concentration increases in both the feeding artery and the vein draining the contracting skeletal muscle. Adenosine also stimulates the formation of NO and prostaglandins, but the plasma adenosine...

  10. Effects of heated hydrotherapy on muscle HSP70 and glucose metabolism in old and young vervet monkeys.

    Science.gov (United States)

    Kavanagh, Kylie; Davis, Ashely T; Jenkins, Kurt A; Flynn, D Mickey

    2016-07-01

    Increasing heat shock protein 70 (HSP70) in aged and/or insulin-resistant animal models confers benefits to healthspan and lifespan. Heat application to increase core temperature induces HSPs in metabolically important tissues, and preliminary human and animal data suggest that heated hydrotherapy is an effective method to achieve increased HSPs. However, safety concerns exist, particularly in geriatric medicine where organ and cardiovascular disease commonly will preexist. We evaluated young vervet monkeys compared to old, insulin-resistant vervet monkeys (Chlorocebus aethiops sabaeus) in their core temperatures, glucose tolerance, muscle HSP70 level, and selected safety biomarkers after 10 sessions of hot water immersions administered twice weekly. Hot water immersion robustly induced the heat shock response in muscles. We observed that heat-treated old and young monkeys have significantly higher muscle HSP70 than control monkeys and treatment was without significant adverse effects on organ or cardiovascular health. Heat therapy improved pancreatic responses to glucose challenge and tended to normalize glucose excursions. A trend for worsened blood pressure and glucose values in the control monkeys and improved values in heat-treated monkeys were seen to support further investigation into the safety and efficacy of this intervention for metabolic syndrome or diabetes in young or old persons unable to exercise.

  11. Photobiomodulation in human muscle tissue: an advantage in sports performance?

    Science.gov (United States)

    Ferraresi, Cleber; Huang, Ying-Ying; Hamblin, Michael R

    2016-12-01

    Photobiomodulation (PBM) describes the use of red or near-infrared (NIR) light to stimulate, heal, and regenerate damaged tissue. Both preconditioning (light delivered to muscles before exercise) and PBM applied after exercise can increase sports performance in athletes. This review covers the effects of PBM on human muscle tissue in clinical trials in volunteers related to sports performance and in athletes. The parameters used were categorized into those with positive effects or no effects on muscle performance and recovery. Randomized controlled trials and case-control studies in both healthy trained and untrained participants, and elite athletes were retrieved from MEDLINE up to 2016. Performance metrics included fatigue, number of repetitions, torque, hypertrophy; measures of muscle damage and recovery such as creatine kinase and delayed onset muscle soreness. Searches retrieved 533 studies, of which 46 were included in the review (n = 1045 participants). Studies used single laser probes, cluster of laser diodes, LED clusters, mixed clusters (lasers and LEDs), and flexible LED arrays. Both red, NIR, and red/NIR mixtures were used. PBM can increase muscle mass gained after training, and decrease inflammation and oxidative stress in muscle biopsies. We raise the question of whether PBM should be permitted in athletic competition by international regulatory authorities. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Robotic Powered Transfer Mechanism modeling on Human Muscle Structure

    Science.gov (United States)

    Saito, Yukio

    It is considered in engineering that one power source can operate one joint. However, support movement mechanism of living organism is multi joint movement mechanism. Considerably different from mechanical movement mechanism, two pairs of uni-articular muscles and a pair of bi-articular muscles are involved in it. In leg, movements observed in short run including leg idling, heel contact and toeing are operated by bi-articular muscles of the thigh showing strong legs to support body weight. Pursuit of versatility in welfare robot brings its comparison with conventional machinery or industrial robot to the fore. Request for safety and technology allowing elderly people to operate the robot is getting stronger in the society. The robot must be safe when it is used together with other welfare equipment and simpler system avoiding difficult operation has to be constructed. Appearance of recent care and assistance robot is getting similar to human arm in comparison with industrial robot. Being easily able to imagine from industrial robot, mid-heavyweight articulated robot to support 60-70kgf combined with large output motor and reduction gears is next to impossible to be installed in the bath room. This research indicated that upper limb arm and lower limb thigh of human and animals are holding coalitional muscles and movement of uni-artcular muscle and bi-articular muscle conjure the image of new actuators.

  13. Development of digastric muscles in human fetuses: a review and findings in the flexor digitorum superficialis muscle.

    Science.gov (United States)

    Rodríguez-Vázquez, José Francisco; Jin, Zhe Wu; Zhao, Peng; Murakami, Gen; Li, Xiang Wu; Jin, Yu

    2017-09-04

    The digastricus and omohyoideus muscles are digastric muscles with two muscle bellies. An insertion tendon of the posterior belly becomes an intermediate tendon in digastricus muscles, whereas a single band-like muscle in omohyoideus muscles may later be interrupted by an intermediate tendon, possibly due to muscle cell death caused by mechanical stress. In human fetuses, an intermediate tendon provides the temporal origins of the tensor veli palatini and tensor tympani muscles. Some reptiles, including snakes, carry multiple series of digastric-like axial muscles, in which each intersegmental septum is likely to become an intermediate tendon. These findings indicate that many pathways are involved in the development of digastric muscles. A review of these morphologies suggested that the flexor digitorum superficialis (FDS) muscle was a digastric muscle, although the intermediate tendon may not be visible in the surface view in adults. The present observations support the hypothesis that the proximal anlage at the elbow develops into a deep muscle slip to a limited finger, while the distal anlage at the wrist develops into the other slips. The findings suggest that, in the FDS muscle, the proximal and distal bellies of the embryonic digastric muscle fuse together to form a laminar structure, in which muscle slips accumulate from the palmar to the deep side of the forearm.

  14. Metabolic Effects of the Very-Low-Carbohydrate Diets: Misunderstood "Villains" of Human Metabolism

    Directory of Open Access Journals (Sweden)

    Manninen Anssi H

    2004-12-01

    Full Text Available Abstract During very low carbohydrate intake, the regulated and controlled production of ketone bodies causes a harmless physiological state known as dietary ketosis. Ketone bodies flow from the liver to extra-hepatic tissues (e.g., brain for use as a fuel; this spares glucose metabolism via a mechanism similar to the sparing of glucose by oxidation of fatty acids as an alternative fuel. In comparison with glucose, the ketone bodies are actually a very good respiratory fuel. Indeed, there is no clear requirement for dietary carbohydrates for human adults. Interestingly, the effects of ketone body metabolism suggest that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. Also, the recent landmark study showed that a very-low-carbohydrate diet resulted in a significant reduction in fat mass and a concomitant increase in lean body mass in normal-weight men. Contrary to popular belief, insulin is not needed for glucose uptake and utilization in man. Finally, both muscle fat and carbohydrate burn in an amino acid flame.

  15. Determination of human muscle protein fractional synthesis rate

    DEFF Research Database (Denmark)

    Bornø, Andreas; Hulston, Carl J; van Hall, Gerrit

    2014-01-01

    In the present study, different MS methods for the determination of human muscle protein fractional synthesis rate (FSR) using [ring-(13)C6 ]phenylalanine as a tracer were evaluated. Because the turnover rate of human skeletal muscle is slow, only minute quantities of the stable isotopically...... labeled amino acid will be incorporated within the few hours of a typical laboratory experiment. GC combustion isotope ratio MS (GC-C-IRMS) has thus far been considered the 'gold' standard for the precise measurements of these low enrichment levels. However, advances in liquid chromatography-tandem MS (LC...

  16. Has cervical smooth muscle any physiological role in the human?

    Science.gov (United States)

    Bryman, I; Norström, A; Lindblom, B

    1985-01-01

    Strips of human cervical tissue were obtained by needle biopsy and contractile activity was registered isometrically in a tissue chamber perfused by Krebs-Ringer bicarbonate buffer. The most frequently encountered pattern of contractile activity was high frequency-short duration. Prostaglandin (PG)E2, PGI2 and 6-keto-PGF1 alpha had an inhibitory effect on the muscular activity. Cervical muscle from pregnant women was more sensitive to PGE2 than specimens from non-pregnant women. PGF2 alpha had no apparent effect on cervical contractility in non-pregnant and early pregnant patients. In late pregnancy, however, PGF2 alpha inhibited muscle contractions. The present results point to a physiological role of the cervical muscles for the control of cervical competence during pregnancy. The inhibitory effect of PGs on the muscle activity may promote cervical dilatation and retraction.

  17. Xanthine oxidase in human skeletal muscle following eccentric exercise

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Frandsen, Ulrik; Orthenblad, N.

    1997-01-01

    1. The present study tested the hypothesis that the level of xanthine oxidase is elevated in injured human skeletal muscle in association with inflammatory events. Seven male subjects performed five bouts of strenuous one-legged eccentric exercise. Muscle biopsies from both the exercised...... and the control leg, together with venous blood samples, were obtained prior to exercise and at 45 min, 24, 48 and 96 h after exercise. The time courses of xanthine oxidase immunoreactivity and indicators of muscle damage and inflammation were examined. 2. The number of xanthine oxidase structures observed...... by immunohistological methods in the exercised muscle was up to eightfold higher than control from day 1 to day 4 after exercise (P

  18. Training affects muscle phospholipid fatty acid composition in humans

    DEFF Research Database (Denmark)

    Helge, Jørn Wulff; Wu, B J; Willer, Mette

    2001-01-01

    Training improves insulin sensitivity, which in turn may affect performance by modulation of fuel availability. Insulin action, in turn, has been linked to specific patterns of muscle structural lipids in skeletal muscle. This study investigated whether regular exercise training exerts an effect...... on the muscle membrane phospholipid fatty acid composition in humans. Seven male subjects performed endurance training of the knee extensors of one leg for 4 wk. The other leg served as a control. Before, after 4 days, and after 4 wk, muscle biopsies were obtained from the vastus lateralis. After 4 wk......, the phospholipid fatty acid contents of oleic acid 18:1(n-9) and docosahexaenoic acid 22:6(n-3) were significantly higher in the trained (10.9 +/- 0.5% and 3.2 +/- 0.4% of total fatty acids, respectively) than the untrained leg (8.8 +/- 0.5% and 2.6 +/- 0.4%, P

  19. Exercise-induced metallothionein expression in human skeletal muscle fibres

    DEFF Research Database (Denmark)

    Penkowa, Milena; Keller, Pernille; Keller, Charlotte

    2005-01-01

    in response to 3 h of bicycle exercise performed by healthy men and in resting controls. Both MT-I + II proteins and MT-II mRNA expression increased significantly in both type I and II muscle fibres after exercise. Moreover, 24 h after exercise the levels of MT-II mRNA and MT-I + II proteins were still highly...... in both type I and II muscle fibres. This is the first report demonstrating that MT-I + II are significantly induced in human skeletal muscle fibres following exercise. As MT-I + II are antioxidant factors that protect various tissues during pathological conditions, the MT-I + II increases post exercise...... may represent a mechanism whereby contracting muscle fibres are protected against cellular stress and injury....

  20. Impaired muscle AMPK activation in the metabolic syndrome may attenuate improved insulin action after exercise training.

    Science.gov (United States)

    Layne, Andrew S; Nasrallah, Sami; South, Mark A; Howell, Mary E A; McCurry, Melanie P; Ramsey, Michael W; Stone, Michael H; Stuart, Charles A

    2011-06-01

    Strength training induces muscle remodeling and may improve insulin responsiveness. This study will quantify the impact of resistance training on insulin sensitivity in subjects with the metabolic syndrome and correlate this with activation of intramuscular pathways mediating mitochondrial biogenesis and muscle fiber hypertrophy. Ten subjects with the metabolic syndrome (MS) and nine sedentary controls underwent 8 wk of supervised resistance exercise training with pre- and posttraining anthropometric and muscle biochemical assessments. Resistance exercise training took place in a sports laboratory on a college campus. Pre- and posttraining insulin responsiveness was quantified using a euglycemic clamp. Changes in expression of muscle 5-AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathways were quantified using immunoblots. Strength and stamina increased in both groups. Insulin sensitivity increased in controls (steady-state glucose infusion rate = 7.0 ± 2.0 mg/kg · min pretraining training vs. 8.7 ± 3.1 mg/kg · min posttraining; P < 0.01) but did not improve in MS subjects (3.3 ± 1.3 pre vs. 3.1 ± 1.0 post). Muscle glucose transporter 4 increased 67% in controls and 36% in the MS subjects. Control subjects increased muscle phospho-AMPK (43%), peroxisome proliferator-activated receptor γ coactivator 1α (57%), and ATP synthase (60%), more than MS subjects (8, 28, and 21%, respectively). In contrast, muscle phospho-mTOR increased most in the MS group (57 vs. 32%). Failure of resistance training to improve insulin responsiveness in MS subjects was coincident with diminished phosphorylation of muscle AMPK, but increased phosphorylation of mTOR, suggesting activation of the mTOR pathway could be involved in inhibition of exercise training-related increases in AMPK and its activation and downstream events.

  1. Re-evaluation of sarcolemma injury and muscle swelling in human skeletal muscles after eccentric exercise.

    Science.gov (United States)

    Yu, Ji-Guo; Liu, Jing-Xia; Carlsson, Lena; Thornell, Lars-Eric; Stål, Per S

    2013-01-01

    The results regarding the effects of unaccustomed eccentric exercise on muscle tissue are often conflicting and the aetiology of delayed onset muscle soreness (DOMS) induced by eccentric exercise is still unclear. This study aimed to re-evaluate the paradigm of muscular alterations with regard to muscle sarcolemma integrity and fibre swelling in human muscles after voluntary eccentric exercise leading to DOMS. Ten young males performed eccentric exercise by downstairs running. Biopsies from the soleus muscle were obtained from 6 non-exercising controls, 4 exercised subjects within 1 hour and 6 exercised subjects at 2-3 days and 7-8 days after the exercise. Muscle fibre sarcolemma integrity, infiltration of inflammatory cells and changes in fibre size and fibre phenotype composition as well as capillary supply were examined with specific antibodies using enzyme histochemistry and immunohistochemistry. Although all exercised subjects experienced DOMS which peaked between 1.5 to 2.5 days post exercise, no significant sarcolemma injury or inflammation was detected in any post exercise group. The results do not support the prevailing hypothesis that eccentric exercise causes an initial sarcolemma injury which leads to subsequent inflammation after eccentric exercise. The fibre size was 24% larger at 7-8 days than at 2-3 days post exercise (pmuscle is not directly associated with the symptom of DOMS.

  2. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans.

    Directory of Open Access Journals (Sweden)

    Anthony E Civitarese

    2007-03-01

    Full Text Available Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood.The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 +/- 1.0 y, overweight (body mass index, 27.8 +/- 0.7 kg/m(2 individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX, 12.5% CR + 12.5% increased energy expenditure (EE. In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, -135 +/- 42 kcal/d, p = 0.002 and CREX, -117 +/- 52 kcal/d, p = 0.008. Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05. In parallel, mitochondrial DNA content increased by 35% +/- 5% in the CR group (p = 0.005 and 21% +/- 4% in the CREX group (p < 0.004, with no change in the control group (2% +/- 2%. However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid cycle (citrate synthase, beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase, and electron transport chain (cytochrome C oxidase II was unchanged. DNA damage was reduced from baseline in the CR (-0.56 +/- 0.11 arbitrary units, p = 0.003 and CREX (-0.45 +/- 0.12 arbitrary units, p = 0.011, but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR.The observed increase in

  3. Muscle fatigue changes cutaneous suppression of propriospinal drive to human upper limb muscles.

    Science.gov (United States)

    Martin, P G; Gandevia, S C; Taylor, J L

    2007-04-01

    Some voluntary drive reaches human upper limb muscles via cervical propriospinal premotoneurones. Stimulation of the superficial radial nerve can inhibit these premotoneurones selectively and the resultant suppression of voluntary drive to motoneurones changes on-going electromyographic (EMG) activity. We investigated whether muscle fatigue changes this cutaneous-induced suppression of propriospinal drive to motoneurones of upper limb muscles. EMG was recorded from the extensors and flexors of the wrist and elbow. In the first study (n = 10 subjects), single stimuli (2 x perception threshold; 2PT) to the superficial radial nerve were delivered during contraction of the wrist extensors, before and after sustained fatiguing contractions of wrist extensors. In the second study (n = 10), similar stimuli were applied during elbow extension, before and during fatigue of elbow extensors. In the final study (n = 10), trains of three stimuli (2PT) were delivered during contractions of wrist extensors, before and while they were fatigued. With fatigue of either the wrist or elbow extensors, EMG suppression to single cutaneous stimuli increased significantly (by approximately 75%) for the fatigued muscle (P muscles, which were coactivated but not principally involved in the task, inhibition decreased or facilitation increased. Trains of stimuli produced greater suppression of on-going wrist extensor EMG than single stimuli and this difference persisted with fatigue. A control study of the H reflex in extensor carpi radialis showed that the mechanism responsible for the altered EMG suppression in fatigue was not at a motoneurone level. The findings suggest that the proportion of descending drive mediated via the disynaptic propriospinal pathway or the excitability of inhibitory interneurones projecting to propriospinal neurones increases substantially to fatigued muscles, but decreases to other active muscles. This pattern of changes may maintain coordination during

  4. Influence of exercise contraction mode and protein supplementation on human skeletal muscle satellite cell content and muscle fiber growth

    DEFF Research Database (Denmark)

    Farup, Jean; Rahbek, Stine Klejs; Riis, Simon

    2014-01-01

    Skeletal muscle satellite cells (SCs) are involved in remodeling and hypertrophy processes of skeletal muscle. However, little knowledge exists on extrinsic factors that influence the content of SCs in skeletal muscle. In a comparative human study, we investigated the muscle fiber type...... CSA increased exclusively with Whey-Conc (P hypertrophy correlated with whole muscle hypertrophy exclusively following Conc training (P ...-specific association between emergence of satellite cells (SCs), muscle growth, and remodeling in response to 12 wk unilateral resistance training performed as eccentric (Ecc) or concentric (Conc) resistance training ± whey protein (Whey, 19.5 g protein + 19.5 g glucose) or placebo (Placebo, 39 g glucose...

  5. Nutrition and muscle loss in humans during spaceflight

    Science.gov (United States)

    Stein, T. P.

    1999-01-01

    The protein loss in humans during spaceflight is partly due to a normal adaptive response to a decreased work load on the muscles involved in weight bearing. The process is mediated by changes in prostaglandin release, secondary to the decrease in tension on the affected muscles. On missions, where there is a high level of physical demands on the astronauts, there tends to be an energy deficit, which adds to the muscle protein loss and depletes the body fat reserves. While the adaptive response is a normal part of homeostasis, the additional protein loss from an energy deficit can, in the long run, have a negative effect on health and capability of humans to live and work in space and afterward return to Earth.

  6. Effect of season on contractile and metabolic properties of desert camel muscle (Camelus dromedarius).

    Science.gov (United States)

    Abdelhadi, O M A; Babiker, S A; Picard, B; Jurie, C; Jailler, R; Hocquette, J F; Faye, B

    2012-01-01

    Thirty fattened one humped desert camels were used to examine the effect of season on contractile and metabolic properties of Longissimus thoracis (LT) muscle. Ten camels were slaughtered according to seasons of the year (winter, summer and autumn). Season significantly influenced muscle chemical composition, ultimate pH (pHu) and color. Activities of metabolic enzymes were higher during autumn season compared to summer and winter for phosphofructokinase (+64% compared to both seasons) and for isocitrate dehydrogenase (+35% and +145% in autumn vs. summer and winter, respectively). Quantification of muscle myosin heavy chain isoforms by SDS-PAGE electrophoresis showed only presence of type I and type IIa MyHC in camel muscle and indicated high proportion in winter for type I and in autumn for type IIa with respect to other seasons. Several correlations between different MyHC proportions and enzyme activities were reported. These findings indicated that muscle characteristics in camels are influenced by season. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues.

    Science.gov (United States)

    Chai, Chofit; Rivkin, Mila; Berkovits, Liav; Simerzin, Alina; Zorde-Khvalevsky, Elina; Rosenberg, Nofar; Klein, Shiri; Yaish, Dayana; Durst, Ronen; Shpitzen, Shoshana; Udi, Shiran; Tam, Joseph; Heeren, Joerg; Worthmann, Anna; Schramm, Christoph; Kluwe, Johannes; Ravid, Revital; Hornstein, Eran; Giladi, Hilla; Galun, Eithan

    2017-11-01

    Effective treatments are needed for hepatic steatosis characterized by accumulation of triglycerides in hepatocytes, which leads to hepatocellular carcinoma. MicroRNA 122 (MIR122) is expressed only in the liver, where it regulates lipid metabolism. We investigated the mechanism by which free fatty acids (FFAs) regulate MIR122 expression and the effect of MIR122 on triglyceride synthesis. We analyzed MIR122 promoter activity and validated its target mRNAs by transfection of Luciferase reporter plasmids into Huh7, BNL-1ME, and HEK293 cultured cell lines. We measured levels of microRNAs and mRNAs by quantitative real-time PCR analysis of RNA extracted from plasma, liver, muscle, and adipose tissues of C57BL/6 mice given the FFA-inducer CL316243. MIR122 was inhibited using an inhibitor of MIR122. Metabolic profiles of mice were determined using metabolic chambers and by histologic analyses of liver tissues. We performed RNA sequence analyses to identify metabolic pathways involving MIR122. We validated human Agpat1 and Dgat1 mRNAs, involved in triglyceride synthesis, as targets of MIR122. FFAs increased MIR122 expression in livers of mice by activating the retinoic acid-related orphan receptor alpha, and induced secretion of MIR122 from liver to blood. Circulating MIR122 entered muscle and adipose tissues of mice, reducing mRNA levels of genes involved in triglyceride synthesis. Mice injected with an inhibitor of MIR122 and then given CL316243, accumulated triglycerides in liver and muscle tissues, and had reduced rates of β-oxidation. There was a positive correlation between level of FFAs and level of MIR122 in plasma samples from 6 healthy individuals, collected before and during fasting. In biochemical and histologic studies of plasma, liver, muscle, and adipose tissues from mice, we found that FFAs increase hepatic expression and secretion of MIR122, which regulates energy storage vs expenditure in liver and peripheral tissues. Strategies to reduce

  8. Bone blood flow and metabolism in humans

    DEFF Research Database (Denmark)

    Heinonen, Ilkka; Kemppainen, Jukka; Kaskinoro, Kimmo

    2012-01-01

    Human bone blood flow and metabolism during physical exercise remains poorly characterised. In the present study we measured femoral bone blood flow and glucose uptake in young healthy subjects by positron emission tomography in three separate protocols. In six women, blood flow was measured...... in femoral bone at rest and during one leg intermittent isometric exercise with increasing exercise intensities. In nine men, blood flow in femur was determined at rest and during dynamic one leg exercise, and two other physiological perturbations: moderate systemic hypoxia (14 O(2) ) at rest and during...... exercise, and during intra-femoral infusion of high-dose adenosine. Bone glucose uptake was measured at rest and during dynamic one leg exercise in five men. The results indicate that isometric exercise increased femoral bone blood flow from rest (1.8 ± 0.6 ml/100g/min) to low intensity exercise (4.1 ± 1...

  9. Stereoselectivity in the human metabolism of methamphetamine.

    Science.gov (United States)

    Li, Linghui; Everhart, Tom; Jacob Iii, Peyton; Jones, Reese; Mendelson, John

    2010-02-01

    To characterize the formation and urinary elimination of metabolites of S-(+) and R-(-) methamphetamine (MA) in humans. In this 12-subject, six-session, double-blind, placebo-controlled, balanced, crossover design study, the formation of the MA metabolites para hydroxymethamphetamine (pOH-MA) and amphetamine (AMP) were determined in urine after intravenous doses of S-(+)-MA 0.25 and 0.5 mg kg(-1), R-(-)-MA 0.25 and 0.5 mg kg(-1), racemic MA 0.5 mg kg(-1), or placebo. Parent drug and metabolite levels in urine and plasma were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental models using WinNonlin. An approximately threefold enantioselectivity difference in elimination was observed for AMP, with 7% of the dose converted to S-(+)-AMP vs. 2% to R-(-)-AMP (P biomarker of MA metabolism.

  10. Effect of dietary glycemic index on substrate transporter gene expression in human skeletal muscle after exercise.

    Science.gov (United States)

    Cheng, I-S; Liao, S-F; Liu, K-L; Liu, H-Y; Wu, C-L; Huang, C-Y; Mallikarjuna, K; Smith, R W; Kuo, C-H

    2009-12-01

    Skeletal muscle plays important role in the regulation of whole-body metabolism. In skeletal muscle, uptakes of glucose and fatty acid from circulation are facilitated by transmembrane substrate transporters GLUT4 and FAT/CD36, respectively. The aim of this study was to determine the effect of dietary glycemic index (GI) on GLUT4 and FAT/CD36 gene expressions in human skeletal muscle after a single bout of exercise. Eight male subjects completed a 60-min cycling exercise at 75% maximal oxygen consumption (VO(2 max)), and were immediately fed an isocaloric meal containing either high-GI (HGI) or low-GI (LGI) diets, with similar proportions of carbohydrate, fat and protein in a crossover design. Muscle samples from deep vastus lateralis were taken by needle biopsy immediately after exercise and 3 h after exercise. After exercise, the HGI diet produced significantly greater glucose and insulin responses compared with the LGI diet, as indicated by the greater area under the curves. Both diets resulted in rapid reductions in plasma fatty acid and glycerol below fasting level. GLUT4 mRNA was downregulated by both HGI and LGI diets to a comparable extent, whereas GLUT4 protein levels were not changed during this short period. FAT/CD36 mRNA and protein levels were substantially decreased with the HGI diet below baseline, but not with the LGI diet. This study found a significant dietary GI effect on post-exercise FAT/CD36 gene expression in human skeletal muscle. This result implicates that the differences in dietary GI are sufficient to alter fat metabolism.

  11. The reconstruction and analysis of tissue specific human metabolic networks.

    Science.gov (United States)

    Hao, Tong; Ma, Hong-Wu; Zhao, Xue-Ming; Goryanin, Igor

    2012-02-01

    Human tissues have distinct biological functions. Many proteins/enzymes are known to be expressed only in specific tissues and therefore the metabolic networks in various tissues are different. Though high quality global human metabolic networks and metabolic networks for certain tissues such as liver have already been studied, a systematic study of tissue specific metabolic networks for all main tissues is still missing. In this work, we reconstruct the tissue specific metabolic networks for 15 main tissues in human based on the previously reconstructed Edinburgh Human Metabolic Network (EHMN). The tissue information is firstly obtained for enzymes from Human Protein Reference Database (HPRD) and UniprotKB databases and transfers to reactions through the enzyme-reaction relationships in EHMN. As our knowledge of tissue distribution of proteins is still very limited, we replenish the tissue information of the metabolic network based on network connectivity analysis and thorough examination of the literature. Finally, about 80% of proteins and reactions in EHMN are determined to be in at least one of the 15 tissues. To validate the quality of the tissue specific network, the brain specific metabolic network is taken as an example for functional module analysis and the results reveal that the function of the brain metabolic network is closely related with its function as the centre of the human nervous system. The tissue specific human metabolic networks are available at .

  12. Spaceflight and protein metabolism, with special reference to humans

    Science.gov (United States)

    Stein, T. P.; Gaprindashvili, T.

    1994-01-01

    Human space missions have shown that human spaceflight is associated with a loss of body protein. Specific changes include a loss of lean body mass, decreased muscle mass in the calves, decreased muscle strength, and changes in plasma proteins and amino acids. The major muscle loss is believed to be associated with the antigravity (postural) muscle. The most significant loss of protein appears to occur during the first month of flight. The etiology is believed to be multifactorial with contributions from disuse atrophy, undernutrition, and a stress type of response. This article reviews the results of American and Russian space missions to investigate this problem in humans, monkeys, and rats. The relationship of the flight results with ground-based models including bedrest for humans and hindlimb unweighting for rats is also discussed. The results suggest that humans adapt to spaceflight much better than either monkeys or rats.

  13. Prospective heterotopic ossification progenitors in adult human skeletal muscle

    NARCIS (Netherlands)

    Downey, Jennifer; Lauzier, Dominique; Kloen, Peter; Klarskov, Klaus; Richter, Martin; Hamdy, Reggie; Faucheux, Nathalie; Scimè, Anthony; Balg, Frédéric; Grenier, Guillaume

    2015-01-01

    Skeletal muscle has strong regenerative capabilities. However, failed regeneration can lead to complications where aberrant tissue forms as is the case with heterotopic ossification (HO), in which chondrocytes, osteoblasts and white and brown adipocytes can arise following severe trauma. In humans,

  14. Length dependent potentiation in electrically stimulated human ankle dorsiflexor muscles

    NARCIS (Netherlands)

    Mela, P.; Veltink, P.H.; Huijing, P.A.J.B.M.

    2002-01-01

    The purpose of this study was to investigate the short-term history effect of a decreasing frequency train on force and the influence of joint angle on such effect in human dorsiflexor muscles. Six able-bodied and three spinal cord injured (SCI) subjects took part in the study. Their isometric left

  15. Muscle mitochondrial capacity exceeds maximal oxygen delivery in humans

    DEFF Research Database (Denmark)

    Boushel, Robert Christopher; Gnaiger, Erich; Calbet, Jose A L

    2011-01-01

    Across a wide range of species and body mass a close matching exists between maximal conductive oxygen delivery and mitochondrial respiratory rate. In this study we investigated in humans how closely in-vivo maximal oxygen consumption (VO(2) max) is matched to state 3 muscle mitochondrial respira...

  16. Selective activation of neuromuscular compartments within the human trapezius muscle

    DEFF Research Database (Denmark)

    Holtermann, A; Roeleveld, K; Mork, P J

    2009-01-01

    was to investigate whether subdivisions within the human trapezius can be independently activated by voluntary command using biofeedback guidance. Bipolar electromyographical electrodes were situated on four subdivisions of the trapezius muscle. The threshold for "active" and "rest" for each subdivision was set...

  17. Acute administration of grape seed proanthocyanidin extract modulates energetic metabolism in skeletal muscle and BAT mitochondria.

    Science.gov (United States)

    Pajuelo, D; Díaz, S; Quesada, H; Fernández-Iglesias, A; Mulero, M; Arola-Arnal, A; Salvadó, M J; Bladé, C; Arola, L

    2011-04-27

    Proanthocyanidin consumption might reduce the risk of developing several pathologies, such as inflammation, oxidative stress and cardiovascular diseases. The beneficial effects of proanthocyanidins are attributed to their antioxidant properties, although they also can modulate gene expression at the transcriptional level. Little is known about the effect of proanthocyanidins on mitochondrial function and energy metabolism. In this context, the objective of this study was to determine the effect of an acute administration of grape seed proanthocyanidin extract (GSPE) on mitochondrial function and energy metabolism. To examine this effect, male Wistar rats fasted for fourteen hours, and then they were orally administered lard oil containing GSPE or were administered lard oil only. Liver, muscle and brown adipose tissue (BAT) were used to study enzymatic activity and gene expression of proteins related to energetic metabolism. Moreover, the gastrocnemius muscle and BAT mitochondria were used to perform high-resolution respirometry. The results showed that, after 5 h, the GSPE administration significantly lowers plasma triglycerides, free fatty acids, glycerol and urea concentrations. In skeletal muscle, GSPE lowers FATP1 mRNA levels and increases mitochondrial oxygen consumption, using pyruvate as the substrate, suggesting a promotion of glycosidic metabolism. Furthermore, GSPE increased the genetic expression of key genes in energy metabolism such as peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α), and modulated the enzyme activity of proteins, which are involved in the citric acid cycle and electron transport chain (ETC) in BAT. In conclusion, GSPE affects mainly the skeletal muscle and BAT mitochondria, increasing their oxidative capacity rapidly after acute supplementation.

  18. Ultrastructure of interstitial cells of Cajal in circular muscle of human small intestine

    DEFF Research Database (Denmark)

    Rumessen, J J; Mikkelsen, H B; Qvortrup, Klaus

    1993-01-01

    Interstitial cells of Cajal (ICC) may be important regulatory cells in gut muscle layers. This study examined ICC within the circular muscle of human small intestine.......Interstitial cells of Cajal (ICC) may be important regulatory cells in gut muscle layers. This study examined ICC within the circular muscle of human small intestine....

  19. Role of muscle IL-6 in gender-specific metabolism in mice.

    Directory of Open Access Journals (Sweden)

    Amalia Molinero

    Full Text Available The aim of the present work was to further explore the physiological roles of muscle-derived IL-6. Adult-floxed and conditional skeletal muscle IL-6 knock out male and female mice were used to study energy expenditure (indirect calorimetry at rest and during treadmill exercise, and body temperature cycle during the light phase and energy intake (response to fast/refeeding. We also evaluated the responses to leptin and the activity of the insulin signalling pathway in skeletal muscle and liver by phosphorylation of Akt at Ser 473. The stress response was also studied. Results indicate a relevant role of muscle IL-6 in maintaining energy homeostasis, especially in males. Absence of muscle IL-6 in male mice results in lower core body temperature in the light phase, increased respiratory exchange ratio (RER both at rest and during exercise, increased expression of TCA cycle marked gene, citrate synthase in muscle, reduced fat storage and decreased body weight and food consumption in response to leptin. In females, muscle IL-6 deficiency increases VO2 and CO2 levels similarly. Also in contrast to males, energy expenditure (EE measured over 48h reveals a significant elevation in female mice with muscle IL-6 deficiency; moreover, they show a modified response to fasting-refeeding and to restraint stress. The present results contribute to the understanding of the role of muscle IL-6 in male and female mouse metabolism, not only during exercise but also in the basal state and in situations where energy balance is altered.

  20. Co-expression Network Approach Reveals Functional Similarities among Diseases Affecting Human Skeletal Muscle

    Directory of Open Access Journals (Sweden)

    Kavitha Mukund

    2017-12-01

    Full Text Available Diseases affecting skeletal muscle exhibit considerable heterogeneity in intensity, etiology, phenotypic manifestation and gene expression. Systems biology approaches using network theory, allows for a holistic understanding of functional similarities amongst diseases. Here we propose a co-expression based, network theoretic approach to extract functional similarities from 20 heterogeneous diseases comprising of dystrophinopathies, inflammatory myopathies, neuromuscular, and muscle metabolic diseases. Utilizing this framework we identified seven closely associated disease clusters with 20 disease pairs exhibiting significant correlation (p < 0.05. Mapping the diseases onto a human protein-protein interaction network enabled the inference of a common program of regulation underlying more than half the muscle diseases considered here and referred to as the “protein signature.” Enrichment analysis of 17 protein modules identified as part of this signature revealed a statistically non-random dysregulation of muscle bioenergetic pathways and calcium homeostasis. Further, analysis of mechanistic similarities of less explored significant disease associations [such as between amyotrophic lateral sclerosis (ALS and cerebral palsy (CP] using a proposed “functional module” framework revealed adaptation of the calcium signaling machinery. Integrating drug-gene information into the quantitative framework highlighted the presence of therapeutic opportunities through drug repurposing for diseases affecting the skeletal muscle.

  1. Immune Response and Mitochondrial Metabolism Are Commonly Deregulated in DMD and Aging Skeletal Muscle

    Science.gov (United States)

    Ramstein, Gérard; Steenman, Marja; Fayet, Guillemette; Chevalier, Catherine; Jourdon, Philippe; Houlgatte, Rémi; Savagner, Frédérique; Pereon, Yann

    2011-01-01

    Duchenne Muscular Dystrophy (DMD) is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed), of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1) or the mitochondrial metabolism (ESRRA). Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors. PMID:22096509

  2. Transgenic Muscle-Specific Nor-1 Expression Regulates Multiple Pathways That Effect Adiposity, Metabolism, and Endurance

    Science.gov (United States)

    Pearen, Michael A.; Goode, Joel M.; Fitzsimmons, Rebecca L.; Eriksson, Natalie A.; Thomas, Gethin P.; Cowin, Gary J.; Wang, S.-C. Mary; Tuong, Zewen K.

    2013-01-01

    The mRNA encoding Nor-1/NR4A3 is rapidly and strikingly induced by β2-adrenergic signaling in glycolytic and oxidative skeletal muscle. In skeletal muscle cells, Nor-1 expression is important for the regulation of oxidative metabolism. Transgenic skeletal muscle-specific expression of activated Nor-1 resulted in the acquisition of an endurance phenotype, an increase in type IIA/X oxidative muscle fibers, and increased numbers of mitochondria. In the current study, we used dual-energy x-ray absorptiometry and magnetic resonance imaging analysis to demonstrate decreased adiposity in transgenic (Tg) Nor-1 mice relative to that in wild-type littermates. Furthermore, the Tg-Nor-1 mice were resistant to diet-induced weight gain and maintained fasting glucose at normoglycemic levels. Expression profiling and RT-quantitative PCR analysis revealed significant increases in genes involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, and glycogen synthesis, in concordance with the lean phenotype. Moreover, expression profiling identified several Z-disc and sarcomeric binding proteins that modulate fiber type phenotype and endurance, eg, α-actinin-3. In addition, we demonstrated that the Tg-Nor-1 mouse line has significantly higher glycogen content in skeletal muscle relative to that in wild-type littermates. Finally, we identified a decreased NAD+/NADH ratio with a concordant increase in peroxisome proliferator-activated receptor γ coactivator-1α1 protein/mRNA expression. Increased NADH was associated with an induction of the genes involved in the malate-aspartate shuttle and a decrease in the glycerol 3-phosphate shuttle, which maximizes aerobic ATP production. In conclusion, skeletal muscle-specific Nor-1 expression regulates genes and pathways that regulate adiposity, muscle fiber type metabolic capacity, and endurance. PMID:24065705

  3. Immune response and mitochondrial metabolism are commonly deregulated in DMD and aging skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Daniel Baron

    Full Text Available Duchenne Muscular Dystrophy (DMD is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed, of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1 or the mitochondrial metabolism (ESRRA. Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors.

  4. Evidence that humans metabolize benzene via two pathways.

    NARCIS (Netherlands)

    Rappaport, S.M.; Kim, S.; Lan, Q.; Vermeulen, R.C.H.; Waidyanatha, S.; Zhang, L.; Li, G.; Yin, S.; Hayes, R.B.; Rothman, N.; Smith, M.T.

    2009-01-01

    BACKGROUND: Recent evidence has shown that humans metabolize benzene more efficiently at environmental air concentrations than at concentrations > 1 ppm. This led us to speculate that an unidentified metabolic pathway was mainly responsible for benzene metabolism at ambient levels. OBJECTIVE: We

  5. Possible Muscle Repair in the Human Cardiovascular System.

    Science.gov (United States)

    Sommese, Linda; Zullo, Alberto; Schiano, Concetta; Mancini, Francesco P; Napoli, Claudio

    2017-04-01

    The regenerative potential of tissues and organs could promote survival, extended lifespan and healthy life in multicellular organisms. Niches of adult stemness are widely distributed and lead to the anatomical and functional regeneration of the damaged organ. Conversely, muscular regeneration in mammals, and humans in particular, is very limited and not a single piece of muscle can fully regrow after a severe injury. Therefore, muscle repair after myocardial infarction is still a chimera. Recently, it has been recognized that epigenetics could play a role in tissue regrowth since it guarantees the maintenance of cellular identity in differentiated cells and, therefore, the stability of organs and tissues. The removal of these locks can shift a specific cell identity back to the stem-like one. Given the gradual loss of tissue renewal potential in the course of evolution, in the last few years many different attempts to retrieve such potential by means of cell therapy approaches have been performed in experimental models. Here we review pathways and mechanisms involved in the in vivo repair of cardiovascular muscle tissues in humans. Moreover, we address the ongoing research on mammalian cardiac muscle repair based on adult stem cell transplantation and pro-regenerative factor delivery. This latter issue, involving genetic manipulations of adult cells, paves the way for developing possible therapeutic strategies in the field of cardiovascular muscle repair.

  6. Skeletal muscle responses to lower limb suspension in humans

    Science.gov (United States)

    Hather, Bruce M.; Adams, Gregory R.; Tesch, Per A.; Dudley, Gary A.

    1992-01-01

    The morphological responses of human skeletal muscle to unweighting were assessed by analyzing multiple transaxial magnetic resonance (MR) images of both lower limbs and skeletal muscle biopsies of the unweighted lower limb before and after six weeks of unilaterial (left) lower limb suspension (ULLS). Results indicated that, as a results of 6 weeks of unweighting (by the subjects walking on crutches using only one limb), the cross sectional area (CSA) of the thigh muscle of the unweighted left limb decreased 12 percent, while the CSA of the right thigh muscle did not change. The decrease was due to a twofold greater response of the knee extensors than the knee flexors. The pre- and post-ULLS biopsies of the left vastus lateralis showed a 14 percent decrease in average fiber CSA due to unweighting. The number of capillaries surrounding the different fiber types was unchanged after ULLS. Results showed that the adaptive responses of human skeletal muscle to unweighting are qualitatively, but not quantitatively, similar to those of lower mammals and not necessarily dependent on the fiber-type composition.

  7. The effects of muscle mass and muscle quality on cardio-metabolic risk in peripubertal girls: a longitudinal study from childhood to early adulthood.

    Science.gov (United States)

    Cheng, S; Wiklund, P

    2017-10-30

    Increased cardio-metabolic risk is well documented in children and adolescents with obesity and normal weight obesity (NWO). However, the associations of muscle mass and muscle quality with cardio-metabolic risk, independent of weight status from childhood to adulthood, has not been examined. A total of 236 girls were followed from pre-puberty to early adulthood. Fat mass (FM) and lean mass (LM) of the whole body were assessed by a dual-energy X-ray absorptiometry; muscle cross-sectional area (mCSA), muscle density (mDen; skeletal muscle fat content) of the lower leg by the peripheral quantitative computerized tomography; and blood glucose, insulin, triglycerides and high-density lipoprotein cholesterol by enzymatic photometric methods. Study participants were categorized based on body mass index (BMI) and percentage body fat (%BF) as overweight and/or obese (BMI⩾30 with %BF⩾30), normal weight obese (BMI 18.5-24.9 with %BF⩾30) and normal weight lean (BMI 18.5-24.9 with %BF cardio-metabolic risk score (r 2 =0.012, Pcardio-metabolic risk factors during pubertal growth after adjusting for measures of adiposity. Ectopic fat accumulation in the skeletal muscle and increased adiposity, particularly in the abdominal area in childhood, are significant contributors to increased cardio-metabolic risk in adulthood, irrespective of body weight status.International Journal of Obesity advance online publication, 28 November 2017; doi:10.1038/ijo.2017.267.

  8. Re-evaluation of sarcolemma injury and muscle swelling in human skeletal muscles after eccentric exercise.

    Directory of Open Access Journals (Sweden)

    Ji-Guo Yu

    Full Text Available The results regarding the effects of unaccustomed eccentric exercise on muscle tissue are often conflicting and the aetiology of delayed onset muscle soreness (DOMS induced by eccentric exercise is still unclear. This study aimed to re-evaluate the paradigm of muscular alterations with regard to muscle sarcolemma integrity and fibre swelling in human muscles after voluntary eccentric exercise leading to DOMS. Ten young males performed eccentric exercise by downstairs running. Biopsies from the soleus muscle were obtained from 6 non-exercising controls, 4 exercised subjects within 1 hour and 6 exercised subjects at 2-3 days and 7-8 days after the exercise. Muscle fibre sarcolemma integrity, infiltration of inflammatory cells and changes in fibre size and fibre phenotype composition as well as capillary supply were examined with specific antibodies using enzyme histochemistry and immunohistochemistry. Although all exercised subjects experienced DOMS which peaked between 1.5 to 2.5 days post exercise, no significant sarcolemma injury or inflammation was detected in any post exercise group. The results do not support the prevailing hypothesis that eccentric exercise causes an initial sarcolemma injury which leads to subsequent inflammation after eccentric exercise. The fibre size was 24% larger at 7-8 days than at 2-3 days post exercise (p<0.05. In contrast, the value of capillary number per fibre area tended to decrease from 2-3 days to 7-8 days post exercise (lower in 5 of the 6 subjects at 7-8 days than at 2-3 days; p<0.05. Thus, the increased fibre size at 7-8 days post exercise was interpreted to reflect fibre swelling. Because the fibre swelling did not appear at the time that DOMS peaked (between 1.5 to 2.5 days post exercise, we concluded that fibre swelling in the soleus muscle is not directly associated with the symptom of DOMS.

  9. Chlamydia pneumoniae induces aponecrosis in human aortic smooth muscle cells

    Directory of Open Access Journals (Sweden)

    Walch Michael

    2005-01-01

    Full Text Available Abstract Background The intracellular bacterium Chlamydia pneumoniae is suspected to play a role in formation and progression of atherosclerosis. Many studies investigated cell death initiation versus inhibition by Chlamydia pneumoniae in established cell lines but nothing is known in primary human aortic smooth muscle cells, a cell type among others known to be involved in the formation of the atherosclerotic plaque. Type of cell death was analyzed by various methods in primary aortic smooth muscle cells after infection with Chlamydia pneumoniae to investigate a possible pathogenic link in atherosclerosis. Results Chlamydiae were found to be localized up to 72 h post infection in aortic smooth muscle cells either as single bacteria or inside of large inclusions. Quantification of host cell death by lactate dehydrogenase release assay revealed strictly dose and time dependent lysis for all tested isolates of Chlamydia pneumoniae. Phosphatidylserine exposure was detected by flow cytometry in Chlamydia pneumoniae infected cells. Ultrastructure of Chlamydia pneumoniae infected human aortic smooth muscle cells showed extensive membrane- and organelle damage, chromatin condensation but no nuclear fragmentation. DNA fragmentation as well as cell membrane permeability was analyzed by TUNEL and NHS-biotin staining and occurred exclusively in cells carrying Chlamydia pneumoniae spots but not in smooth muscle cells with inclusions. These morphological features of cell death were not accompanied by an activation of caspase-3 as revealed by analysis of enzyme activity but involved mitochondrial membrane depolarization as shown by TMRE uptake and release of cytochrome c from mitochondria. Conclusion This study provides evidence that Chlamydia pneumoniae induce a spot like infection in human aortic smooth muscle cells, which results in a chimeric cell death with both apoptotic and necrotic characteristics. This aponecrotic cell death may assist chronic

  10. Myostatin promotes distinct responses on protein metabolism of skeletal and cardiac muscle fibers of rodents

    Directory of Open Access Journals (Sweden)

    L.H. Manfredi

    2017-10-01

    Full Text Available Myostatin is a novel negative regulator of skeletal muscle mass. Myostatin expression is also found in heart in a much less extent, but it can be upregulated in pathological conditions, such as heart failure. Myostatin may be involved in inhibiting protein synthesis and/or increasing protein degradation in skeletal and cardiac muscles. Herein, we used cell cultures and isolated muscles from rats to determine protein degradation and synthesis. Muscles incubated with myostatin exhibited an increase in proteolysis with an increase of Atrogin-1, MuRF1 and LC3 genes. Extensor digitorum longus muscles and C2C12 myotubes exhibited a reduction in protein turnover. Cardiomyocytes showed an increase in proteolysis by activating autophagy and the ubiquitin proteasome system, and a decrease in protein synthesis by decreasing P70S6K. The effect of myostatin on protein metabolism is related to fiber type composition, which may be associated to the extent of atrophy mediated effect of myostatin on muscle.

  11. Muscle metabolism of professional athletes using {sup 31}P-spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Maeurer, J.; Soellner, O.; Ehrenstein, T.; Knollmann, F.; Vogl, T.J.; Felix, R. [Humboldt-Universitaet, Berlin (Germany). Strahlenklinik und Poliklinik; Konstanczak, P. [Medizinische Univ. Luebeck (Germany). Inst. fuer Radiologie; Wolff, R. [Humboldt-Universitaet Berlin (Germany). Dept. of Sports Medicine

    1999-01-01

    Purpose: The aim of the study was to examine muscle metabolism in athletes by {sup 31}P-spectroscopy (MRS) and to evaluate to what degree the respective resonance spectrum correlates with the kind of muscle exercise. Material and Methods: Twelve runners and 12 young ice skaters were studied by {sup 31}P-spectroscopy of the gastrocnemic medialis muscle and the vastus medialis muscle using a surface coil at 1.5 T. Results: Sprinters displayed a higher phosphocreatinine/inorganic phosphate (PCr/Pi) and PCr/{beta}-ATP ratios than marathon runners. The respective parameters for middle distance runners were in between. Ice skaters could prospectively be divided into sprint- and long-distance runners by our results which correlated with the athletes` training performance. Conclusion: {sup 31}P-spectroscopy can evaluate the distribution of muscle fiber types. Thus, the athlete`s potential for sprint- or long-distance running can be determined. Additional studies will have to demonstrate to what extent training may change muscle fiber distribution. (orig.)

  12. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

    Science.gov (United States)

    Stump, Craig S.; Short, Kevin R.; Bigelow, Maureen L.; Schimke, Jill M.; Sreekumaran Nair, K.

    2003-06-01

    Mitochondria are the primary site of skeletal muscle fuel metabolism and ATP production. Although insulin is a major regulator of fuel metabolism, its effect on mitochondrial ATP production is not known. Here we report increases in vastus lateralis muscle mitochondrial ATP production capacity (32-42%) in healthy humans (P growth hormone. Increased ATP production occurred in association with increased mRNA levels from both mitochondrial (NADH dehydrogenase subunit IV) and nuclear [cytochrome c oxidase (COX) subunit IV] genes (164-180%) encoding mitochondrial proteins (P muscle mitochondrial protein synthesis, and COX and citrate synthase enzyme activities were increased by insulin (P muscle mitochondrial ATP production for people with type 2 diabetes mellitus, whereas matched nondiabetic controls increased 16-26% (P muscle along with synthesis of gene transcripts and mitochondrial protein in human subjects. Skeletal muscle of type 2 diabetic patients has a reduced capacity to increase ATP production with high insulin levels. cytochrome c oxidase | NADH dehydrogenase subunit IV | amino acids | citrate synthase

  13. Physical inactivity and muscle oxidative capacity in humans

    DEFF Research Database (Denmark)

    Gram, Martin; Dahl, Rannvá; Dela, Flemming

    2014-01-01

    of proteins related to oxidative phosphorylation. With such a substantial down-regulation, it is likely that a range of adenosine triphosphate (ATP)-dependent pathways such as calcium signalling, respiratory capacity and apoptosis are affected by physical inactivity. However, this has not been investigated...... in humans, and further studies are required to substantiate this hypothesis, which could expand our knowledge of the potential link between lifestyle-related diseases and muscle oxidative capacity. Furthermore, even though a large body of literature reports the effect of physical training on muscle...

  14. Inhibitory action of relaxin on human cervical smooth muscle.

    Science.gov (United States)

    Norström, A; Bryman, I; Wiqvist, N; Sahni, S; Lindblom, B

    1984-09-01

    The influence of purified porcine relaxin on contractility of human cervical smooth muscle was investigated in vitro. Strips of cervical tissue were obtained by needle biopsy from pregnant and nonpregnant women and were mounted in a superfused organ chamber for isometric measurement of contractile activity. Relaxin (0.005-25 micrograms/ml) inhibited the spontaneous contractions in cervical strips from 18% of nonpregnant, 68% of early pregnant, and in 100% of term pregnant women. These results indicate that relaxin has an inhibitory action on cervical smooth muscle and that this effect is more constantly detected as pregnancy proceeds.

  15. Eicosapentaenoic acid improves metabolic switching in human myotubes

    NARCIS (Netherlands)

    Hessvik, Nina P.; Bakke, Siril S.; Fredriksson, Katarina; Boekschoten, Mark; Fjorkenstad, Anne; Koster, Gerbrand; Hesselink, Matthijs K.; Kersten, Sander; Kase, Eili T.; Rustan, Arild C.; Thoresen, Hege

    2010-01-01

    Metabolically healthy skeletal muscle is characterized by the ability to switch easily between glucose and fat oxidation, whereas loss of this ability seems to be related to insulin resistance. The aim of this study was to investigate whether different fatty acids (FAs) and the LXR ligand T0901317

  16. A compendium of inborn errors of metabolism mapped onto the human metabolic network.

    Science.gov (United States)

    Sahoo, Swagatika; Franzson, Leifur; Jonsson, Jon J; Thiele, Ines

    2012-10-01

    Inborn errors of metabolism (IEMs) are hereditary metabolic defects, which are encountered in almost all major metabolic pathways occurring in man. Many IEMs are screened for in neonates through metabolomic analysis of dried blood spot samples. To enable the mapping of these metabolomic data onto the published human metabolic reconstruction, we added missing reactions and pathways involved in acylcarnitine (AC) and fatty acid oxidation (FAO) metabolism. Using literary data, we reconstructed an AC/FAO module consisting of 352 reactions and 139 metabolites. When this module was combined with the human metabolic reconstruction, the synthesis of 39 acylcarnitines and 22 amino acids, which are routinely measured, was captured and 235 distinct IEMs could be mapped. We collected phenotypic and clinical features for each IEM enabling comprehensive classification. We found that carbohydrate, amino acid, and lipid metabolism were most affected by the IEMs, while the brain was the most commonly affected organ. Furthermore, we analyzed the IEMs in the context of metabolic network topology to gain insight into common features between metabolically connected IEMs. While many known examples were identified, we discovered some surprising IEM pairs that shared reactions as well as clinical features but not necessarily causal genes. Moreover, we could also re-confirm that acetyl-CoA acts as a central metabolite. This network based analysis leads to further insight of hot spots in human metabolism with respect to IEMs. The presented comprehensive knowledge base of IEMs will provide a valuable tool in studying metabolic changes involved in inherited metabolic diseases.

  17. PDH regulation in skeletal muscle

    DEFF Research Database (Denmark)

    Kiilerich, Kristian

    regulation in human skeletal muscle. 2: Effect of muscle glycogen on PDH regulation in human skeletal muscle at rest and during exercise. 3: The impact of physical inactivity on PDH regulation in human skeletal muscle at rest and during exercise. 4: Elucidating the importance of PGC-1? in PDH regulation...... in mouse skeletal muscle at rest and in response to fasting and during recovery from exercise. The studies indicate that the content of PDH-E1? in human muscle follows the metabolic profile of the muscle, rather than the myosin heavy chain fiber distribution of the muscle. The larger lactate accumulation...... in human skeletal muscle. It may be noted that the increased PDK4 protein associated with elevated plasma FFA occurs already 2 hours after different dietary intake. A week of physical inactivity (bed rest), leading to whole body glucose intolerance, does not affect muscle PDH-E1? content, or the exercise...

  18. Integrated analysis of chronic lipotoxicity on muscle metabolism and stress and its reversal by antioxidants.

    Science.gov (United States)

    Verma, Mahesh Kumar; Yateesh, Aggunda Nagaraju; Smitha, Rachapalli; Neelima, Korrapati; Pallavi, Puttrevana M; Reddy, Madhusudhan; Poornima, Jayaram; Oommen, Anup M; Jagannath, Madanahalli R; Somesh, Baggavalli P

    2014-01-01

    Apart from elevated glucose, triglyceride and cholesterol, elevated levels of serum free-fatty acid (FFA) are observed in diabetic patients. Increased FFA load can cause multiple dysregulation which are collectively known as lipotoxicity. Impacts of FFA induced lipotoxicity were evaluated on various cellular responses of metabolism and stress in skeletal muscle myotubes. Under lipotoxicity, oxidative capacity of C2C12 myotubes was reduced and decreased levels ATP and NAD were observed. Lipotoxicity augmented non-oxidative disposal of metabolites in terms of lactate release, IMTG and ceramide synthesis. Concomitantly, insulin resistance was also observed. These impacts were in conjunction with increased cellular stress, inflammation, proteolysis and apoptosis. Quenching of lipotoxicity mediated oxidative stress by antioxidant reverted its deleterious impacts and restored insulin stimulated glucose uptake. In conclusion, the in vitro lipotoxicity makes a system which resembles in vivo pathology of muscle as seen in diabetic patients and represents an integrated perspective of lipotoxicity on various parameters of metabolism and stress.

  19. Elevated mitochondrial oxidative stress impairs metabolic adaptations to exercise in skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Justin D Crane

    Full Text Available Mitochondrial oxidative stress is a complex phenomenon that is inherently tied to energy provision and is implicated in many metabolic disorders. Exercise training increases mitochondrial oxidative capacity in skeletal muscle yet it remains unclear if oxidative stress plays a role in regulating these adaptations. We demonstrate that the chronic elevation in mitochondrial oxidative stress present in Sod2 (+/- mice impairs the functional and biochemical mitochondrial adaptations to exercise. Following exercise training Sod2 (+/- mice fail to increase maximal work capacity, mitochondrial enzyme activity and mtDNA copy number, despite a normal augmentation of mitochondrial proteins. Additionally, exercised Sod2 (+/- mice cannot compensate for their higher amount of basal mitochondrial oxidative damage and exhibit poor electron transport chain complex assembly that accounts for their compromised adaptation. Overall, these results demonstrate that chronic skeletal muscle mitochondrial oxidative stress does not impact exercise induced mitochondrial biogenesis, but impairs the resulting mitochondrial protein function and can limit metabolic plasticity.

  20. Pronounced effects of accute endurance exercise on gene expression in resting and exercising human skeletal muscle

    NARCIS (Netherlands)

    Catoire, M.; Mensink, M.R.; Boekschoten, M.V.; Hangelbroek, R.W.J.; Muller, M.R.; Schrauwen, P.; Kersten, A.H.

    2012-01-01

    Regular physical activity positively influences whole body energy metabolism and substrate handling in exercising muscle. While it is recognized that the effects of exercise extend beyond exercising muscle, it is unclear to what extent exercise impacts non-exercising muscles. Here we investigated

  1. mTORC2 Regulation of Muscle Metabolism and Insulin Sensitivity

    DEFF Research Database (Denmark)

    Kleinert, Maximilian

    by defects in the insulin signaling chain necessary for glucose uptake. To better understand the underlying molecular mechanisms of how mTORC2 regulates metabolism in skeletal muscle, we performed unbiased, global quantitative phospho- and total proteomic analyses of mouse Ric mKO muscles. This revealed......Type 2 diabetes (T2D) is a pandemic that continues to grow at alarming rates. In healthy individuals, blood glucose levels are tightly controlled. After eating a meal blood glucose levels rise. This triggers insulin release from the pancreas, which in turn signals organs like the liver, fat...... and skeletal muscle to take up blood glucose, ultimately lowering blood glucose levels. A hallmark of T2D is decreased organ sensitivity to the effects of the insulin. Therefore, an early event in the pathogenesis of T2D is an increase in insulin secretion in response to eating a meal, as more insulin...

  2. Expression of muscle anabolic and metabolic factors in mechanically loaded MLO-Y4 osteocytes.

    Science.gov (United States)

    Juffer, Petra; Jaspers, Richard T; Lips, Paul; Bakker, Astrid D; Klein-Nulend, Jenneke

    2012-02-15

    Lack of physical activity results in muscle atrophy and bone loss, which can be counteracted by mechanical loading. Similar molecular signaling pathways are involved in the adaptation of muscle and bone mass to mechanical loading. Whether anabolic and metabolic factors regulating muscle mass, i.e., insulin-like growth factor-I isoforms (IGF-I Ea), mechano growth factor (MGF), myostatin, vascular endothelial growth factor (VEGF), or hepatocyte growth factor (HGF), are also produced by osteocytes in bone in response to mechanical loading is largely unknown. Therefore, we investigated whether mechanical loading by pulsating fluid flow (PFF) modulates the mRNA and/or protein levels of muscle anabolic and metabolic factors in MLO-Y4 osteocytes. Unloaded MLO-Y4 osteocytes expressed mRNA of VEGF, HGF, IGF-I Ea, and MGF, but not myostatin. PFF increased mRNA levels of IGF-I Ea (2.1-fold) and MGF (2.0-fold) at a peak shear stress rate of 44Pa/s, but not at 22Pa/s. PFF at 22 Pa/s increased VEGF mRNA levels (1.8- to 2.5-fold) and VEGF protein release (2.0- to 2.9-fold). Inhibition of nitric oxide production decreased (2.0-fold) PFF-induced VEGF protein release. PFF at 22 Pa/s decreased HGF mRNA levels (1.5-fold) but increased HGF protein release (2.3-fold). PFF-induced HGF protein release was nitric oxide dependent. Our data show that mechanically loaded MLO-Y4 osteocytes differentially express anabolic and metabolic factors involved in the adaptive response of muscle to mechanical loading (i.e., IGF-I Ea, MGF, VEGF, and HGF). Similarly to muscle fibers, mechanical loading enhanced expression levels of these growth factors in MLO-Y4 osteocytes. Although in MLO-Y4 osteocytes expression levels of IGF-I Ea and MGF of myostatin were very low or absent, it is known that the activity of osteoblasts and osteoclasts is strongly affected by them. The abundant expression levels of these factors in muscle cells, in combination with low expression in MLO-Y4 osteocytes, provide a

  3. Sodium nitrate ingestion increases skeletal muscle nitrate content in humans.

    Science.gov (United States)

    Nyakayiru, Jean; Kouw, Imre W K; Cermak, Naomi M; Senden, Joan M; van Loon, Luc J C; Verdijk, Lex B

    2017-09-01

    Nitrate ([Formula: see text]) ingestion has been shown to have vasoactive and ergogenic effects that have been attributed to increased nitric oxide (NO) production. Recent observations in rodents suggest that skeletal muscle tissue serves as an endogenous [Formula: see text] "reservoir." The present study determined [Formula: see text] contents in human skeletal muscle tissue in a postabsorptive state and following ingestion of a sodium nitrate bolus (NaNO 3 ). Seventeen male, type 2 diabetes patients (age 72 ± 1 yr; body mass index 26.5 ± 0.5 kg/m 2 ; means ± SE) were randomized to ingest a dose of NaNO 3 (NIT; 9.3 mg [Formula: see text]/kg body wt) or placebo (PLA; 8.8 mg NaCl/kg body wt). Blood and muscle biopsy samples were taken before and up to 7 h following [Formula: see text] or placebo ingestion to assess [Formula: see text] [and plasma nitrite ([Formula: see text])] concentrations. Additionally, basal plasma and muscle [Formula: see text] concentrations were assessed in 10 healthy young (CON-Y; age 21 ± 1 yr) and 10 healthy older (CON-O; age 75 ± 1 yr) control subjects. In all groups, baseline [Formula: see text] concentrations were higher in muscle (NIT, 57 ± 7; PLA, 61 ± 7; CON-Y, 80 ± 10; CON-O, 54 ± 6 µmol/l) than in plasma (NIT, 35 ± 3; PLA, 32 ± 3; CON-Y, 38 ± 3; CON-O, 33 ± 3 µmol/l; P ≤ 0.011). Ingestion of NaNO 3 resulted in a sustained increase in plasma [Formula: see text], plasma [Formula: see text], and muscle [Formula: see text] concentrations (up to 185 ± 25 µmol/l) in the NIT group (time effect P nitrate ingestion is usually limited to the changes observed in plasma nitrate and nitrite concentrations. The present investigation assessed the skeletal muscle nitrate content in humans during the postabsorptive state, as well as following dietary nitrate ingestion. We show that basal nitrate content is higher in skeletal muscle tissue than in plasma and that ingestion of a dietary nitrate bolus strongly increases both plasma

  4. ATP economy of force maintenance in human tibialis anterior muscle

    DEFF Research Database (Denmark)

    Nakagawa, Yoshinao; Ratkevicius, Aivaras; Mizuno, Masao

    2005-01-01

    PURPOSE: The aim of this study was investigate ATP economy of force maintenance in the human tibialis anterior muscle during 60 s of anaerobic voluntary contraction at 50% of maximum voluntary contraction (MVC). METHODS: ATP turnover rate was evaluated using P magnetic resonance spectroscopy (P......) of the total ankle dorsiflexor muscle volume, which was 267 +/- 10 cm. Relative cross-sectional areas occupied by Type I, IIA, and IIB fibers in the tibialis anterior were 69.3 +/- 2.2, 27.4 +/- 2.76, and 3.2 +/- 1.0%, respectively. ATP economy of force maintenance did not change significantly during the 60-s...... contraction. It averaged at 4.81 +/- 0.42 N.s.micromol-1, and correlated with the relative cross-sectional area of the muscle occupied by Type I fiber (r = 0.73, P economy compared with those maintaining the force (3...

  5. Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells.

    Science.gov (United States)

    Fletcher, Rachel S; Ratajczak, Joanna; Doig, Craig L; Oakey, Lucy A; Callingham, Rebecca; Da Silva Xavier, Gabriella; Garten, Antje; Elhassan, Yasir S; Redpath, Philip; Migaud, Marie E; Philp, Andrew; Brenner, Charles; Canto, Carles; Lavery, Gareth G

    2017-08-01

    Augmenting nicotinamide adenine dinucleotide (NAD + ) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD + precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD + . Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD + from NMN and NR and provide insight into mechanisms of muscle metabolic homeostasis. We exploited expression profiling of muscle NAD + biosynthetic pathways, single and double nicotinamide riboside kinase 1/2 (NRK1/2) loss-of-function mice, and pharmacological inhibition of muscle NAD + recycling to evaluate NMN and NR utilization. Skeletal muscle cells primarily rely on nicotinamide phosphoribosyltransferase (NAMPT), NRK1, and NRK2 for salvage biosynthesis of NAD + . NAMPT inhibition depletes muscle NAD + availability and can be rescued by NR and NMN as the preferred precursors for elevating muscle cell NAD + in a pathway that depends on NRK1 and NRK2. Nrk2 knockout mice develop normally and show subtle alterations to their NAD+ metabolome and expression of related genes. NRK1, NRK2, and double KO myotubes revealed redundancy in the NRK dependent metabolism of NR to NAD + . Significantly, these models revealed that NMN supplementation is also dependent upon NRK activity to enhance NAD + availability. These results identify skeletal muscle cells as requiring NAMPT to maintain NAD + availability and reveal that NRK1 and 2 display overlapping function in salvage of exogenous NR and NMN to augment intracellular NAD + availability.

  6. Selective upregulation of lipid metabolism in skeletal muscle of foraging juvenile king penguins: an integrative study.

    Science.gov (United States)

    Teulier, Loic; Dégletagne, Cyril; Rey, Benjamin; Tornos, Jérémy; Keime, Céline; de Dinechin, Marc; Raccurt, Mireille; Rouanet, Jean-Louis; Roussel, Damien; Duchamp, Claude

    2012-06-22

    The passage from shore to marine life of juvenile penguins represents a major energetic challenge to fuel intense and prolonged demands for thermoregulation and locomotion. Some functional changes developed at this crucial step were investigated by comparing pre-fledging king penguins with sea-acclimatized (SA) juveniles (Aptenodytes patagonicus). Transcriptomic analysis of pectoralis muscle biopsies revealed that most genes encoding proteins involved in lipid transport or catabolism were upregulated, while genes involved in carbohydrate metabolism were mostly downregulated in SA birds. Determination of muscle enzymatic activities showed no changes in enzymes involved in the glycolytic pathway, but increased 3-hydroxyacyl-CoA dehydrogenase, an enzyme of the β-oxidation pathway. The respiratory rates of isolated muscle mitochondria were much higher with a substrate arising from lipid metabolism (palmitoyl-L-carnitine) in SA juveniles than in terrestrial controls, while no difference emerged with a substrate arising from carbohydrate metabolism (pyruvate). In vivo, perfusion of a lipid emulsion induced a fourfold larger thermogenic effect in SA than in control juveniles. The present integrative study shows that fuel selection towards lipid oxidation characterizes penguin acclimatization to marine life. Such acclimatization may involve thyroid hormones through their nuclear beta receptor and nuclear coactivators.

  7. The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men

    Science.gov (United States)

    Browning, Jeffrey D.; Baxter, Jeannie; Satapati, Santhosh; Burgess, Shawn C.

    2012-01-01

    Fasting promotes triglyceride (TG) accumulation in lean tissues of some animals, but the effect in humans is unknown. Additionally, fasting lipolysis is sexually dimorphic in humans, suggesting that lean tissue TG accumulation and metabolism may differ between women and men. This study investigated lean tissue TG content and metabolism in women and men during extended fasting. Liver and muscle TG content were measured by magnetic resonance spectroscopy during a 48-h fast in healthy men and women. Whole-body and hepatic carbohydrate, lipid, and energy metabolism were also evaluated using biochemical, calorimetric, and stable isotope tracer techniques. As expected, postabsorptive plasma fatty acids (FAs) were higher in women than in men but increased more rapidly in men with the onset of early starvation. Concurrently, sexual dimorphism was apparent in lean tissue TG accumulation during the fast, occurring in livers of men but in muscles of women. Despite differences in lean tissue TG distribution, men and women had identical fasting responses in whole-body and hepatic glucose and oxidative metabolism. In conclusion, TG accumulated in livers of men but in muscles of women during extended fasting. This sexual dimorphism was related to differential fasting plasma FA concentrations but not to whole body or hepatic utilization of this substrate. PMID:22140269

  8. Mechanical stimulation improves tissue-engineered human skeletal muscle

    Science.gov (United States)

    Powell, Courtney A.; Smiley, Beth L.; Mills, John; Vandenburgh, Herman H.

    2002-01-01

    Human bioartificial muscles (HBAMs) are tissue engineered by suspending muscle cells in collagen/MATRIGEL, casting in a silicone mold containing end attachment sites, and allowing the cells to differentiate for 8 to 16 days. The resulting HBAMs are representative of skeletal muscle in that they contain parallel arrays of postmitotic myofibers; however, they differ in many other morphological characteristics. To engineer improved HBAMs, i.e., more in vivo-like, we developed Mechanical Cell Stimulator (MCS) hardware to apply in vivo-like forces directly to the engineered tissue. A sensitive force transducer attached to the HBAM measured real-time, internally generated, as well as externally applied, forces. The muscle cells generated increasing internal forces during formation which were inhibitable with a cytoskeleton depolymerizer. Repetitive stretch/relaxation for 8 days increased the HBAM elasticity two- to threefold, mean myofiber diameter 12%, and myofiber area percent 40%. This system allows engineering of improved skeletal muscle analogs as well as a nondestructive method to determine passive force and viscoelastic properties of the resulting tissue.

  9. Wheal and flare responses to muscle relaxants in humans.

    Science.gov (United States)

    Levy, J H; Adelson, D; Walker, B

    1991-11-01

    Chemically and pharmacologically unrelated molecules release histamine in humans to produce both cutaneous and systemic responses. It has been suggested that molecular changes in the new benzylisoquinoline-derived muscle relaxant, atracurium, make it less likely to cause histamine release. We therefore injected volunteers intradermally with equimolar concentrations of various muscle relaxants, morphine, papaverine (a benzylisoquinoline), and histamine, to evaluate the relative ability of these drugs to cause wheal and flare responses, and mast-cell degranulation. There were no significant differences in wheal and flare responses among the three benzylisoquinoline-derived muscle relaxants, D-tubocurarine, metocurine, and atracurium. The cutaneous effects of morphine were significantly greater than those of the benzylisoquinoline muscle relaxants, suggesting both direct vascular changes and histamine release. Papaverine injection was followed by a significant wheal but no flare. Skin biopsies from vecuronium- and papaverine-induced wheals revealed normal intact mast-cell granules, suggesting a direct cutaneous vascular response rather than histamine release. Skin biopsies after morphine and atracurium injections revealed mast-cell degranulation. All evaluated benzylisoquinoline muscle relaxants are equipotent histamine releasers at equimolar concentrations. A hydrogenated, benzylisoquinoline-nitrogen-containing ring, present in atracurium but not in papaverine, appears to be the molecular conformation responsible for mast-cell degranulation by atracurium.

  10. Smooth Muscle Progenitor Cells Derived From Human Pluripotent Stem Cells Induce Histologic Changes in Injured Urethral Sphincter.

    Science.gov (United States)

    Li, Yanhui; Wen, Yan; Wang, Zhe; Wei, Yi; Wani, Prachi; Green, Morgaine; Swaminathan, Ganesh; Ramamurthi, Anand; Pera, Renee Reijo; Chen, Bertha

    2016-12-01

    embryonic stem cells and patient induced pluripotent stem cells) restores urethral sphincter function by two mechanisms: modulation of extracellular matrix protein metabolism in vivo and pSMC proliferation and differentiation into smooth muscle cells to regenerate the muscle layer in the lower urinary tract. These findings on the in vivo effects of human pSMCs should aid in optimizing regenerative therapies using human myoblasts. ©AlphaMed Press.

  11. Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise

    DEFF Research Database (Denmark)

    Miller, Benjamin F; Olesen, Jens L; Hansen, Mette

    2005-01-01

    in target proteins by gas chromatography-mass spectrometry. Patellar tendon and quadriceps biopsies were taken in exercised and rested legs at 6, 24, 42 or 48 and 72 h after exercise. The fractional synthetic rates of all proteins were elevated at 6 h and rose rapidly to peak at 24 h post exercise (tendon...... in human tendon and muscle. The similar time course of changes of protein synthetic rates in different cell types supports the idea of coordinated musculotendinous adaptation....

  12. Double discharges in human soleus muscle

    Directory of Open Access Journals (Sweden)

    Maria Piotrkiewicz

    2013-12-01

    Full Text Available Double discharges (doublets were recorded from human soleus, where they have never been found before. The data analyzed in this study were collected from 12 healthy volunteers. The subjects were recruited for other studies, concerning: (1 estimation of motoneurons’ afterhyperpolarization duration and (2 analysis of motor unit responses to nerve stimulation, and were not trained to voluntarily evoke doublets. The majority of doublet intervals fell into the commonly accepted range 2–20 ms. However, two soleus motoneurons from one subject presented exceptional doublets of interval about 37 ms. This interval was virtually identical with the interval between second and third discharge in the few triplets recorded from another subject. It is hypothesized that triplets are generated by the delayed depolarization with the second narrow hump, which is the same as the hump responsible for exceptional doublets.

  13. Simulating the physiology of athletes during endurance sports events: modelling human energy conversion and metabolism.

    Science.gov (United States)

    van Beek, Johannes H G M; Supandi, Farahaniza; Gavai, Anand K; de Graaf, Albert A; Binsl, Thomas W; Hettling, Hannes

    2011-11-13

    The human physiological system is stressed to its limits during endurance sports competition events. We describe a whole body computational model for energy conversion during bicycle racing. About 23 per cent of the metabolic energy is used for muscle work, the rest is converted to heat. We calculated heat transfer by conduction and blood flow inside the body, and heat transfer from the skin by radiation, convection and sweat evaporation, resulting in temperature changes in 25 body compartments. We simulated a mountain time trial to Alpe d'Huez during the Tour de France. To approach the time realized by Lance Armstrong in 2004, very high oxygen uptake must be sustained by the simulated cyclist. Temperature was predicted to reach 39°C in the brain, and 39.7°C in leg muscle. In addition to the macroscopic simulation, we analysed the buffering of bursts of high adenosine triphosphate hydrolysis by creatine kinase during cyclical muscle activity at the biochemical pathway level. To investigate the low oxygen to carbohydrate ratio for the brain, which takes up lactate during exercise, we calculated the flux distribution in cerebral energy metabolism. Computational modelling of the human body, describing heat exchange and energy metabolism, makes simulation of endurance sports events feasible.

  14. The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Modifies Exercise-Induced Muscle Metabolism.

    Directory of Open Access Journals (Sweden)

    David Vaughan

    Full Text Available A silencer region (I-allele within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE, is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non-carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle.Fifty-three, not-specifically trained Caucasian men carried out a one-legged bout of cycling exercise to exhaustion and/or participated in a marathon, the aim being to identify and validate genotype effects on exercise metabolism. Respiratory exchange ratio (RER, serum glucose and lipid concentration, glycogen, and metabolite content in vastus lateralis muscle based on ultra-performance lipid chromatography-mass spectrometry (UPLC-MS, were assessed before and after the cycling exercise in thirty-three participants. Serum metabolites were measured in forty subjects that completed the marathon. Genotype effects were assessed post-hoc.Cycling exercise reduced muscle glycogen concentration and this tended to be affected by the ACE I-allele (p = 0.09. The ACE-DD genotype showed a lower maximal RER and a selective increase in serum glucose concentration after exercise compared to ACE-ID and ACE-II genotypes (+24% vs. +2% and -3%, respectively. Major metabolites of mitochondrial metabolism (i.e. phosphoenol pyruvate, nicotinamide adenine dinucleotide phosphate, L-Aspartic acid, glutathione were selectively affected in vastus lateralis muscle by exercise in the ACE-DD genotype. Capillary-to-fibre ratio was 24%-lower in the ACE-DD genotype. Individuals with the ACE-DD genotype demonstrated an abnormal increase in serum glucose to 7.7 mM after the marathon.The observations imply a genetically modulated role for ACE in control of glucose import and oxidation in

  15. The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Modifies Exercise-Induced Muscle Metabolism.

    Science.gov (United States)

    Vaughan, David; Brogioli, Michael; Maier, Thomas; White, Andy; Waldron, Sarah; Rittweger, Jörn; Toigo, Marco; Wettstein, Jessica; Laczko, Endre; Flück, Martin

    2016-01-01

    A silencer region (I-allele) within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE), is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non-carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle. Fifty-three, not-specifically trained Caucasian men carried out a one-legged bout of cycling exercise to exhaustion and/or participated in a marathon, the aim being to identify and validate genotype effects on exercise metabolism. Respiratory exchange ratio (RER), serum glucose and lipid concentration, glycogen, and metabolite content in vastus lateralis muscle based on ultra-performance lipid chromatography-mass spectrometry (UPLC-MS), were assessed before and after the cycling exercise in thirty-three participants. Serum metabolites were measured in forty subjects that completed the marathon. Genotype effects were assessed post-hoc. Cycling exercise reduced muscle glycogen concentration and this tended to be affected by the ACE I-allele (p = 0.09). The ACE-DD genotype showed a lower maximal RER and a selective increase in serum glucose concentration after exercise compared to ACE-ID and ACE-II genotypes (+24% vs. +2% and -3%, respectively). Major metabolites of mitochondrial metabolism (i.e. phosphoenol pyruvate, nicotinamide adenine dinucleotide phosphate, L-Aspartic acid, glutathione) were selectively affected in vastus lateralis muscle by exercise in the ACE-DD genotype. Capillary-to-fibre ratio was 24%-lower in the ACE-DD genotype. Individuals with the ACE-DD genotype demonstrated an abnormal increase in serum glucose to 7.7 mM after the marathon. The observations imply a genetically modulated role for ACE in control of glucose import and oxidation in working

  16. Morphometric and Statistical Analysis of the Palmaris Longus Muscle in Human and Non-Human Primates

    Directory of Open Access Journals (Sweden)

    Roqueline A. G. M. F. Aversi-Ferreira

    2014-01-01

    Full Text Available The palmaris longus is considered a phylogenetic degenerate metacarpophalangeal joint flexor muscle in humans, a small vestigial forearm muscle; it is the most variable muscle in humans, showing variation in position, duplication, slips and could be reverted. It is frequently studied in papers about human anatomical variations in cadavers and in vivo, its variation has importance in medical clinic, surgery, radiological analysis, in studies about high-performance athletes, in genetics and anthropologic studies. Most studies about palmaris longus in humans are associated to frequency or case studies, but comparative anatomy in primates and comparative morphometry were not found in scientific literature. Comparative anatomy associated to morphometry of palmaris longus could explain the degeneration observed in this muscle in two of three of the great apes. Hypothetically, the comparison of the relative length of tendons and belly could indicate the pathway of the degeneration of this muscle, that is, the degeneration could be associated to increased tendon length and decreased belly from more primitive primates to those most derivate, that is, great apes to modern humans. In conclusion, in primates, the tendon of the palmaris longus increase from Lemuriformes to modern humans, that is, from arboreal to terrestrial primates and the muscle became weaker and tending to be missing.

  17. VAPB/ALS8 MSP ligands regulate striated muscle energy metabolism critical for adult survival in caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Sung Min Han

    Full Text Available Mutations in VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS and spinal muscular atrophy (SMA, two motor neuron diseases that often include alterations in energy metabolism. We have shown that C. elegans and Drosophila neurons secrete a cleavage product of VAPB, the N-terminal major sperm protein domain (vMSP. Secreted vMSPs signal through Roundabout and Lar-like receptors expressed on striated muscle. The muscle signaling pathway localizes mitochondria to myofilaments, alters their fission/fusion balance, and promotes energy production. Here, we show that neuronal loss of the C. elegans VAPB homolog triggers metabolic alterations that appear to compensate for muscle mitochondrial dysfunction. When vMSP levels drop, cytoskeletal or mitochondrial abnormalities in muscle induce elevated DAF-16, the Forkhead Box O (FoxO homolog, transcription factor activity. DAF-16 promotes muscle triacylglycerol accumulation, increases ATP levels in adults, and extends lifespan, despite reduced muscle mitochondria electron transport chain activity. Finally, Vapb knock-out mice exhibit abnormal muscular triacylglycerol levels and FoxO target gene transcriptional responses to fasting and refeeding. Our data indicate that impaired vMSP signaling to striated muscle alters FoxO activity, which affects energy metabolism. Abnormalities in energy metabolism of ALS patients may thus constitute a compensatory mechanism counterbalancing skeletal muscle mitochondrial dysfunction.

  18. Differential Effects of Sepsis and Chronic Inflammation on Diaphragm Muscle Fiber Type, Thyroid Hormone Metabolism, and Mitochondrial Function

    NARCIS (Netherlands)

    Bloise, Flavia F.; van der Spek, Anne H.; Surovtseva, Olga V.; Ortiga-Carvalho, Tania Maria; Fliers, Eric; Boelen, Anita

    2016-01-01

    The diaphragm is the main respiratory muscle, and its function is compromised during severe illness. Altered local thyroid hormone (TH) metabolism may be a determinant of impaired muscle function during illness. This study investigates the effects of bacterial sepsis and chronic inflammation on

  19. Effect of BCAA intake during endurance exercises on fatigue substances, muscle damage substances, and energy metabolism substances

    OpenAIRE

    Kim, Dong-Hee; Kim, Seok-Hwan; Jeong, Woo-Seok; Lee, Ha-Yan

    2013-01-01

    The increase rate of utilization of branched-chain amino acids (BCAA) by muscle is reduced to its plasma concentration during prolonged exercise leading to glycogen. BCAA supplementation would reduce the serum activities of intramuscular enzymes associated with muscle damage. To examine the effects of BCAA administration on fatigue substances (serotonin, ammonia and lactate), muscle damage substances (CK and LDH) and energy metabolism substances (FFA and glucose) after endurance exercise. Sub...

  20. Relative Skeletal Muscle Mass Is Associated with Development of Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Byung Sam Park

    2013-12-01

    Full Text Available BackgroundVisceral adiposity is related to insulin resistance. Skeletal muscle plays a central role in insulin-mediated glucose disposal; however, little is known about the association between muscle mass and metabolic syndrome (MS. This study is to clarify the clinical role of skeletal muscle mass in development of MS.MethodsA total of 1,042 subjects were enrolled. Subjects with prior MS and chronic diseases were excluded. After 24 months, development of MS was assessed using NCEP-ATP III criteria. Skeletal muscle mass (SMM; kg, body fat mass (BFM; kg, and visceral fat area (VFA; cm2 were obtained from bioelectrical analysis. Then, the following values were calculated as follows: percent of SMM (SMM%; %: SMM (kg/weight (kg, skeletal muscle index (SMI; kg/m2: SMM (kg/height (m2, skeletal muscle to body fat ratio (MFR: SMM (kg/BFM (kg, and skeletal muscle to visceral fat ratio (SVR; kg/cm2: SMM (kg/VFA (cm2.ResultsAmong 838 subjects, 88 (10.5% were newly diagnosed with MS. Development of MS increased according to increasing quintiles of BMI, SMM, VFA, and SMI, but was negatively associated with SMM%, MFR, and SVR. VFA was positively associated with high waist circumference (WC, high blood pressure (BP, dysglycemia, and high triglyceride (TG. In contrast, MFR was negatively associated with high WC, high BP, dysglycemia, and high TG. SVR was negatively associated with all components of MS.ConclusionRelative SMM ratio to body composition, rather than absolute mass, may play a critical role in development of MS and could be used as a strong predictor.

  1. Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes

    Science.gov (United States)

    Smith, Robert; Solberg, Rigmor; Jacobsen, Linn Løkken; Voreland, Anette Larsen; Rustan, Arild Christian; Thoresen, G. Hege; Johansen, Harald Thidemann

    2014-01-01

    Simvastatin, a HMG-CoA reductase inhibitor, is prescribed worldwide to patients with hypercholesterolemia. Although simvastatin is well tolerated, side effects like myotoxicity are reported. The mechanism for statin-induced myotoxicity is still poorly understood. Reports have suggested impaired mitochondrial dysfunction as a contributor to the observed myotoxicity. In this regard, we wanted to study the effects of simvastatin on glucose metabolism and the activity of legumain, a cysteine protease. Legumain, being the only known asparaginyl endopeptidase, has caspase-like properties and is described to be involved in apoptosis. Recent evidences indicate a regulatory role of both glucose and statins on cysteine proteases in monocytes. Satellite cells were isolated from the Musculus obliquus internus abdominis of healthy human donors, proliferated and differentiated into polynuclear myotubes. Simvastatin with or without mevalonolactone, farnesyl pyrophosphate or geranylgeranyl pyrophosphate were introduced on day 5 of differentiation. After 48 h, cells were either harvested for immunoblotting, ELISA, cell viability assay, confocal imaging or enzyme activity analysis, or placed in a fuel handling system with [14C]glucose or [3H]deoxyglucose for uptake and oxidation studies. A dose-dependent decrease in both glucose uptake and oxidation were observed in mature myotubes after exposure to simvastatin in concentrations not influencing cell viability. In addition, simvastatin caused a decrease in maturation and activity of legumain. Dysregulation of glucose metabolism and decreased legumain activity by simvastatin points out new knowledge about the effects of statins on skeletal muscle, and may contribute to the understanding of the myotoxicity observed by statins. PMID:24416446

  2. Understanding human metabolic physiology: a genome-to-systems approach.

    Science.gov (United States)

    Mo, Monica L; Palsson, Bernhard Ø

    2009-01-01

    The intricate nature of human physiology renders its study a difficult undertaking, and a systems biology approach is necessary to understand the complex interactions involved. Network reconstruction is a key step in systems biology and represents a common denominator because all systems biology research on a target organism relies on such a representation. With the recent development of genome-scale human metabolic networks, metabolic systems analysis is now possible and has initiated a shift towards human systems biology. Here, we review the important aspects of reconstructing a bottom-up human metabolic network, the network's role in modeling human physiology and the necessity for a community-based consensus reconstruction of human metabolism to be established.

  3. Transcriptional Signature of an Altered Purine Metabolism in the Skeletal Muscle of a Huntington's Disease Mouse Model.

    Science.gov (United States)

    Mielcarek, Michal; Smolenski, Ryszard T; Isalan, Mark

    2017-01-01

    Huntington's disease (HD) is a fatal neurodegenerative disorder, caused by a polyglutamine expansion in the huntingtin protein (HTT). HD has a peripheral component to its pathology: skeletal muscles are severely affected, leading to atrophy, and malfunction in both pre-clinical and clinical settings. We previously used two symptomatic HD mouse models to demonstrate the impairment of the contractile characteristics of the hind limb muscles, which was accompanied by a significant loss of function of motor units. The mice displayed a significant reduction in muscle force, likely because of deteriorations in energy metabolism, decreased oxidation, and altered purine metabolism. There is growing evidence suggesting that HD-related skeletal muscle malfunction might be partially or completely independent of CNS degeneration. The pathology might arise from mutant HTT within muscle (loss or gain of function). Hence, it is vital to identify novel peripheral biomarkers that will reflect HD skeletal muscle atrophy. These will be important for upcoming clinical trials that may target HD peripherally. In order to identify potential biomarkers that might reflect muscle metabolic changes, we used qPCR to validate key gene transcripts in different skeletal muscle types. Consequently, we report a number of transcript alterations that are linked to HD muscle pathology.

  4. Blood pressure and the contractility of a human leg muscle

    Science.gov (United States)

    Luu, Billy L; Fitzpatrick, Richard C

    2013-01-01

    These studies investigate the relationships between perfusion pressure, force output and pressor responses for the contracting human tibialis anterior muscle. Eight healthy adults were studied. Changing the height of tibialis anterior relative to the heart was used to control local perfusion pressure. Electrically stimulated tetanic force output was highly sensitive to physiological variations in perfusion pressure showing a proportionate change in force output of 6.5% per 10 mmHg. This perfusion-dependent change in contractility begins within seconds and is reversible with a 53 s time constant, demonstrating a steady-state equilibrium between contractility and perfusion pressure. These stimulated contractions did not produce significant cardiovascular responses, indicating that the muscle pressor response does not play a major role in cardiovascular regulation at these workloads. Voluntary contractions at forces that would require constant motor drive if perfusion pressure had remained constant generated a central pressor response when perfusion pressure was lowered. This is consistent with a larger cortical drive being required to compensate for the lost contractility with lower perfusion pressure. The relationship between contractility and perfusion for this large postural muscle was not different from that of a small hand muscle (adductor pollicis) and it responded similarly to passive peripheral and active central changes in arterial pressure, but extended over a wider operating range of pressures. If we consider that, in a goal-oriented motor task, muscle contractility determines central motor output and the central pressor response, these results indicate that muscle would fatigue twice as fast without a pressor response. From its extent, timing and reversibility we propose a testable hypothesis that this change in contractility arises through contraction- and perfusion-dependent changes in interstitial K+ concentration. PMID:24018946

  5. Specific Physical Exercise Improves Energetic Metabolism in the Skeletal Muscle of Amyotrophic-Lateral- Sclerosis Mice

    Science.gov (United States)

    Desseille, Céline; Deforges, Séverine; Biondi, Olivier; Houdebine, Léo; D’amico, Domenico; Lamazière, Antonin; Caradeuc, Cédric; Bertho, Gildas; Bruneteau, Gaëlle; Weill, Laure; Bastin, Jean; Djouadi, Fatima; Salachas, François; Lopes, Philippe; Chanoine, Christophe; Massaad, Charbel; Charbonnier, Frédéric

    2017-01-01

    Amyotrophic Lateral Sclerosis is an adult-onset neurodegenerative disease characterized by the specific loss of motor neurons, leading to muscle paralysis and death. Although the cellular mechanisms underlying amyotrophic lateral sclerosis (ALS)-induced toxicity for motor neurons remain poorly understood, growing evidence suggest a defective energetic metabolism in skeletal muscles participating in ALS-induced motor neuron death ultimately destabilizing neuromuscular junctions. In the present study, we report that a specific exercise paradigm, based on a high intensity and amplitude swimming exercise, significantly improves glucose metabolism in ALS mice. Using physiological tests and a biophysics approach based on nuclear magnetic resonance (NMR), we unexpectedly found that SOD1(G93A) ALS mice suffered from severe glucose intolerance, which was counteracted by high intensity swimming but not moderate intensity running exercise. Furthermore, swimming exercise restored the highly ALS-sensitive tibialis muscle through an autophagy-linked mechanism involving the expression of key glucose transporters and metabolic enzymes, including GLUT4 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Importantly, GLUT4 and GAPDH expression defects were also found in muscles from ALS patients. Moreover, we report that swimming exercise induced a triglyceride accumulation in ALS tibialis, likely resulting from an increase in the expression levels of lipid transporters and biosynthesis enzymes, notably DGAT1 and related proteins. All these data provide the first molecular basis for the differential effects of specific exercise type and intensity in ALS, calling for the use of physical exercise as an appropriate intervention to alleviate symptoms in this debilitating disease. PMID:29104532

  6. Specific Physical Exercise Improves Energetic Metabolism in the Skeletal Muscle of Amyotrophic-Lateral- Sclerosis Mice

    Directory of Open Access Journals (Sweden)

    Céline Desseille

    2017-10-01

    Full Text Available Amyotrophic Lateral Sclerosis is an adult-onset neurodegenerative disease characterized by the specific loss of motor neurons, leading to muscle paralysis and death. Although the cellular mechanisms underlying amyotrophic lateral sclerosis (ALS-induced toxicity for motor neurons remain poorly understood, growing evidence suggest a defective energetic metabolism in skeletal muscles participating in ALS-induced motor neuron death ultimately destabilizing neuromuscular junctions. In the present study, we report that a specific exercise paradigm, based on a high intensity and amplitude swimming exercise, significantly improves glucose metabolism in ALS mice. Using physiological tests and a biophysics approach based on nuclear magnetic resonance (NMR, we unexpectedly found that SOD1(G93A ALS mice suffered from severe glucose intolerance, which was counteracted by high intensity swimming but not moderate intensity running exercise. Furthermore, swimming exercise restored the highly ALS-sensitive tibialis muscle through an autophagy-linked mechanism involving the expression of key glucose transporters and metabolic enzymes, including GLUT4 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH. Importantly, GLUT4 and GAPDH expression defects were also found in muscles from ALS patients. Moreover, we report that swimming exercise induced a triglyceride accumulation in ALS tibialis, likely resulting from an increase in the expression levels of lipid transporters and biosynthesis enzymes, notably DGAT1 and related proteins. All these data provide the first molecular basis for the differential effects of specific exercise type and intensity in ALS, calling for the use of physical exercise as an appropriate intervention to alleviate symptoms in this debilitating disease.

  7. Glycolysis is independent of oxygenation state in stimulated human skeletal muscle in vivo

    Science.gov (United States)

    Conley, Kevin E; Kushmerick, Martin J; Jubrias, Sharon A

    1998-01-01

    We tested the hypothesis that the cytoplasmic control mechanism for glycolysis is affected by the presence of oxygen during exercise. We used a comparison of maximal twitch stimulation under ischaemic and intact circulation in human wrist flexor and ankle dorsiflexor muscles. 31P magnetic resonance spectroscopy followed the phosphocreatine (PCr), Pi and pH dynamics at 6–9 s intervals. Glycolytic PCr synthesis was determined during stimulation from pH and tissue buffer capacity, as well as the oxidative phosphorylation rate. Ischaemic vs. aerobic stimulation resulted in similar glycolytic fluxes in the two muscles. The onset of glycolysis occured after fifty to seventy stimulations and the extent of glycolytic PCr synthesis was directly proportional to the number of stimulations thereafter. Two-fold differences in the putative feedback regulators of glycolysis, [Pi] and [ADP], were found between aerobic and ischaemic stimulation. The similar glycolytic fluxes in the face of these differences in metabolite levels eliminates feedback as a control mechanism in glycolysis. These results demonstrate that glycolytic flux is independent of oxygenation state and metabolic feedback, but proportional to muscle activation. These results show a key role for muscle stimulation in the activation and maintenance of glycolysis. Further, this glycolytic control mechanism is independent of the feedback control mechanism that governs oxidative phosphorylation. PMID:9714871

  8. Dietary Exercise as a Novel Strategy for the Prevention and Treatment of Metabolic Syndrome: Effects on Skeletal Muscle Function

    Directory of Open Access Journals (Sweden)

    Wataru Aoi

    2011-01-01

    Full Text Available A sedentary lifestyle can cause metabolic syndrome to develop. Metabolic syndrome is associated with metabolic function in the skeletal muscle, a major consumer of nutrients. Dietary exercise, along with an adequate diet, is reported to be one of the major preventive therapies for metabolic syndrome; exercise improves the metabolic capacity of muscles and prevents the loss of muscle mass. Epidemiological studies have shown that physical activity reduces the risk of various common diseases such as cardiovascular disease, diabetes, and cancer; it also helps in reducing visceral adipose tissue. In addition, laboratory studies have demonstrated the mechanisms underlying the benefits of single-bout and regular exercise. Exercise regulates the expression/activity of proteins associated with metabolic and anabolic signaling in muscle, leading to a change in phenotype. The extent of these changes depends on the intensity, the duration, and the frequency of the exercise. The effect of exercise is also partly due to a decrease in inflammation, which has been shown to be closely related to the development of various diseases. Furthermore, it has been suggested that several phytochemicals contained in natural foods can improve nutrient metabolism and prevent protein degradation in the muscle.

  9. Exercise-Induced Skeletal Muscle Remodeling and Metabolic Adaptation: Redox Signaling and Role of Autophagy

    Science.gov (United States)

    Giammarioli, Anna Maria; Chiandotto, Sergio; Spoletini, Ilaria

    2014-01-01

    Abstract Significance: Skeletal muscle is a highly plastic tissue. Exercise evokes signaling pathways that strongly modify myofiber metabolism and physiological and contractile properties of skeletal muscle. Regular physical activity is beneficial for health and is highly recommended for the prevention of several chronic conditions. In this review, we have focused our attention on the pathways that are known to mediate physical training-induced plasticity. Recent Advances: An important role for redox signaling has recently been proposed in exercise-mediated muscle remodeling and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) activation. Still more currently, autophagy has also been found to be involved in metabolic adaptation to exercise. Critical Issues: Both redox signaling and autophagy are processes with ambivalent effects; they can be detrimental and beneficial, depending on their delicate balance. As such, understanding their role in the chain of events induced by exercise and leading to skeletal muscle remodeling is a very complicated matter. Moreover, the study of the signaling induced by exercise is made even more difficult by the fact that exercise can be performed with several different modalities, with this having different repercussions on adaptation. Future Directions: Unraveling the complexity of the molecular signaling triggered by exercise on skeletal muscle is crucial in order to define the therapeutic potentiality of physical training and to identify new pharmacological compounds that are able to reproduce some beneficial effects of exercise. In evaluating the effect of new “exercise mimetics,” it will also be necessary to take into account the involvement of reactive oxygen species, reactive nitrogen species, and autophagy and their controversial effects. Antioxid. Redox Signal. 21, 154–176. PMID:24450966

  10. Associations of visceral fat, physical activity and muscle strength with the metabolic syndrome.

    Science.gov (United States)

    Bisschop, Charlotte N Steins; Peeters, Petra H M; Monninkhof, Evelyn M; van der Schouw, Yvonne T; May, Anne M

    2013-10-01

    We investigated the association of visceral fat with the metabolic syndrome (MetS) and its separate components; the associations of both physical activity and muscle strength with the MetS and its separate components independent of visceral fat. Furthermore, we studied these associations within participants with low and high amounts of visceral fat. 400 men (aged 40-80 years) were recruited into a cross-sectional study. Logistic regression models were used to study the individual associations in all participants (OR). The associations of physical activity (active vs inactive) and muscle strength (high vs low) within participants with low and high levels of visceral fat (assessed by ultrasonography) were tested using Univariate Analysis of Variance (difference in mean levels of the separate components of MetS) and logistic regression (risk on MetS). High levels of visceral fat were significantly associated with increased risk of MetS (OR 1.7 95%CI 1.5;1.9) and its separate components (pphysical activity or muscle strength, neither within men with low or high levels of visceral fat. High body fat levels were associated with an unhealthier metabolic risk profile and a higher risk of the MetS. Our cross-sectional data do not indicate associations for physical activity or for muscle strength with the MetS independent of visceral fat. Also no differential associations of physical activity or muscle strength in men with low or high levels of visceral fat were found. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Quantitative Anatomy of the Trapezius Muscle in the Human Fetus.

    Science.gov (United States)

    Badura, Mateusz; Grzonkowska, Magdalena; Baumgart, Mariusz; Szpinda, Michał

    2016-01-01

    The trapezius muscle consists of three parts that are capable of functioning independently. Its superior part together with the levator scapulae and rhomboids elevate the shoulder, the middle part retracts the scapula, while the inferior part lowers the shoulder. The present study aimed to supplement numerical data and to provide growth dynamics of the trapezius in the human fetus. Using methods of anatomical dissection, digital image analysis (NIS Elements AR 3.0), and statistics (Student's t-test, regression analysis), we measured the length, the width and the surface area of the trapezius in 30 fetuses of both sexes (13™ k,17™ … ) aged 13-19 weeks. Neither sex nor laterality differences were found. All the studied parameters of the trapezius increased proportionately with age. The linear functions were computed as follows: y = -103.288 + 10.514 × age (r = 0.957) for total length of the trapezius muscle, y = -67.439 + 6.689 × age (r = 0.856) for length of its descending part, y = -8.493 + 1.033 × age (r = 0.53) for length of its transverse part, y = -27.545 + 2.802 × age (r = 0.791) for length of its ascending part, y = -19.970 + 2.505 × age (r = 0.875) for width of the trapezius muscle, and y = -2670.458 + 212.029 × age (r = 0.915) for its surface area. Neither sex nor laterality differences exist in the numerical data of the trapezius muscle in the human fetus. The descending part of trapezius is the longest, while its transverse part is the shortest. The growth dynamics of the fetal trapezius muscle follows proportionately.

  12. Rats bred for low aerobic capacity become promptly fatigued and have slow metabolic recovery after stimulated, maximal muscle contractions.

    Directory of Open Access Journals (Sweden)

    Sira Torvinen

    Full Text Available Muscular fatigue is a complex phenomenon affected by muscle fiber type and several metabolic and ionic changes within myocytes. Mitochondria are the main determinants of muscle oxidative capacity which is also one determinant of muscle fatigability. By measuring the concentrations of intracellular stores of high-energy phosphates it is possible to estimate the energy production efficiency and metabolic recovery of the muscle. Low intrinsic aerobic capacity is known to be associated with reduced mitochondrial function. Whether low intrinsic aerobic capacity also results in slower metabolic recovery of skeletal muscle is not known. Here we studied the influence of intrinsic aerobic capacity on in vivo muscle metabolism during maximal, fatiguing electrical stimulation.Animal subjects were genetically heterogeneous rats selectively bred to differ for non-trained treadmill running endurance, low capacity runners (LCRs and high capacity runners (HCRs (n = 15-19. We measured the concentrations of major phosphorus compounds and force parameters in a contracting triceps surae muscle complex using (31P-Magnetic resonance spectroscopy ((31P-MRS combined with muscle force measurement from repeated isometric twitches.Our results demonstrated that phosphocreatine re-synthesis after maximal muscle stimulation was significantly slower in LCRs (p<0.05. LCR rats also became promptly fatigued and maintained the intramuscular pH poorly compared to HCRs. Half relaxation time (HRT of the triceps surae was significantly longer in LCRs throughout the stimulation protocol (p≤0.05 and maximal rate of torque development (MRTD was significantly lower in LCRs compared to HCRs from 2 min 30 s onwards (p≤0.05.We observed that LCRs are more sensitive to fatigue and have slower metabolic recovery compared to HCRs after maximal muscle contractions. These new findings are associated with reduced running capacity and with previously found lower mitochondrial content, increased

  13. Erythropoietin receptor in human skeletal muscle and the effects of acute and long-term injections with recombinant human erythropoietin on the skeletal muscle

    DEFF Research Database (Denmark)

    Lundby, Carsten; Hellsten, Ylva; Jensen, Mie B. F.

    2008-01-01

    The presence and potential physiological role of the erythropoietin receptor (Epo-R) were examined in human skeletal muscle. In this study we demonstrate that Epo-R is present in the endothelium, smooth muscle cells, and in fractions of the sarcolemma of skeletal muscle fibers. To study...... the potential effects of Epo in human skeletal muscle, two separate studies were conducted: one to study the acute effects of a single Epo injection on skeletal muscle gene expression and plasma hormones and another to study the effects of long-term (14 wk) Epo treatment on skeletal muscle structure. Subjects....... In conclusion, the Epo-R is present in the vasculature and myocytes in human skeletal muscle, suggesting a role in both cell types. In accordance, a single injection of Epo regulates myoglobin, MRF-4, and transferrin receptor mRNA levels. However, in contrast to our hypothesis, prolonged Epo administration had...

  14. Improved neurological outcome by intramuscular injection of human amniotic fluid derived stem cells in a muscle denervation model.

    Directory of Open Access Journals (Sweden)

    Chun-Jung Chen

    Full Text Available The skeletal muscle develops various degrees of atrophy and metabolic dysfunction following nerve injury. Neurotrophic factors are essential for muscle regeneration. Human amniotic fluid derived stem cells (AFS have the potential to secrete various neurotrophic factors necessary for nerve regeneration. In the present study, we assess the outcome of neurological function by intramuscular injection of AFS in a muscle denervation and nerve anastomosis model.Seventy two Sprague-Dawley rats weighing 200-250 gm were enrolled in this study. Muscle denervation model was conducted by transverse resection of a sciatic nerve with the proximal end sutured into the gluteal muscle. The nerve anastomosis model was performed by transverse resection of the sciatic nerve followed by four stitches reconnection. These animals were allocated to three groups: control, electrical muscle stimulation, and AFS groups.NT-3 (Neurotrophin 3, BDNF (Brain derived neurotrophic factor, CNTF (Ciliary neurotrophic factor, and GDNF (Glia cell line derived neurotrophic factor were highly expressed in AFS cells and supernatant of culture medium. Intra-muscular injection of AFS exerted significant expression of several neurotrophic factors over the distal end of nerve and denervated muscle. AFS caused high expression of Bcl-2 in denervated muscle with a reciprocal decrease of Bad and Bax. AFS preserved the muscle morphology with high expression of desmin and acetylcholine receptors. Up to two months, AFS produced significant improvement in electrophysiological study and neurological functions such as SFI (sciatic nerve function index and Catwalk gait analysis. There was also significant preservation of the number of anterior horn cells and increased nerve myelination as well as muscle morphology.Intramuscular injection of AFS can protect muscle apoptosis and likely does so through the secretion of various neurotrophic factors. This protection furthermore improves the nerve

  15. Restrictions in systemic and locomotor skeletal muscle perfusion, oxygen supply and VO2 during high-intensity whole-body exercise in humans

    DEFF Research Database (Denmark)

    Mortensen, S.P.; Damsgaard, R.; Dawson, E.A.

    2008-01-01

    there is an extreme metabolic stimulus to vasodilate during supramaximal exercise remains unknown. To examine the regulatory limits of systemic and muscle perfusion in exercising humans, we measured systemic and leg haemodynamics, O(2) transport, and , and estimated non-locomotor tissue perfusion during constant load...... is restricted during maximal and supramaximal whole-body exercise in association with a plateau in Q and limb vascular conductance. These observations suggest that limits of cardiac function and muscle vasoconstriction underlie the inability of the circulatory system to meet the increasing metabolic demand......Perfusion to exercising skeletal muscle is regulated to match O(2) delivery to the O(2) demand, but this regulation might be compromised during or approaching maximal whole-body exercise as muscle blood flow for a given work rate is blunted. Whether muscle perfusion is restricted when...

  16. Muscle blood flow and muscle metabolism during exercise and heat stress

    DEFF Research Database (Denmark)

    Nielsen, Bodil; Savard, G; Richter, Erik

    1990-01-01

    environment a steady state was reached at 30 min. When the subjects were shifted to the hot room, the core temperature and heart rate started to rise and reached values greater than 39 degrees C and near-maximal values, respectively, at the termination of the exercise. The leg blood flow (thermodilution......The effect of heat stress on blood flow and metabolism in an exercising leg was studied in seven subjects walking uphill (12-17%) at 5 km/h on a treadmill for 90 min or until exhaustion. The first 30 min of exercise were performed in a cool environment (18-21 degrees C); then subjects moved...... to an adjacent room at 40 degrees C and continued to exercise at the same speed and inclination for a further 60 min or to exhaustion, whichever occurred first. The rate of O2 consumption, 2.6 l/min (1.8-3.3) (average from cool and hot conditions), corresponded to 55-77% of their individual maximums. In the cool...

  17. Myostatin blockade with a fully human monoclonal antibody induces muscle hypertrophy and reverses muscle atrophy in young and aged mice

    OpenAIRE

    Latres, Esther; Pangilinan, Jeffrey; Miloscio, Lawrence; Bauerlein, Roy; Na, Erqian; Potocky, Terra B.; Huang, Ying; Eckersdorff, Mark; Rafique, Ashique; Mastaitis, Jason; Lin, Calvin; Murphy, Andrew J.; Yancopoulos, George D.; Gromada, Jesper; Stitt, Trevor

    2015-01-01

    Background Loss of skeletal muscle mass and function in humans is associated with significant morbidity and mortality. The role of myostatin as a key negative regulator of skeletal muscle mass and function has supported the concept that inactivation of myostatin could be a useful approach for treating muscle wasting diseases. Methods We generated a myostatin monoclonal blocking antibody (REGN1033) and characterized its effects in vitro using surface plasmon resonance biacore and cell-based Sm...

  18. Damping actions of the neuromuscular system with inertial loads: human flexor pollicis longus muscle.

    Science.gov (United States)

    Lin, D C; Rymer, W Z

    2001-03-01

    Our previous work in an animal model showed that neuromuscular damping properties help maintain limb posture by effectively dissipating mechanical energy arising from disturbances. The purpose of this study was to determine whether similar damping properties were expressed in intact, normal human muscles. To review briefly, when the reflexively active soleus muscle in a decerebrate cat is coupled to an inertial load, application of a force impulse to the load results in lightly damped oscillations. By calculating the logarithmic decrement in muscle velocity following the impulse (the decrement being related to the amount of energy dissipated from the inertia), we found that damping increased with oscillation amplitude, a nonlinear property. This nonlinearity represents an automatic compensation for larger perturbations. Our findings in parallel experiments on the interphalangeal joint of the human thumb were that the long thumb flexor, the flexor pollicis longus (FPL), displayed mechanical and reflex behavior closely comparable to that reported earlier for the cat soleus, despite differences in architectural and metabolic properties between these muscles. Specifically, by selecting experimental trials that did not include voluntary interventions, we observed amplitude-dependent differences in damping in which larger amplitude movements elicited larger damping than did smaller movements. In addition, even after accounting for amplitude-dependent differences in damping, damping was found to be larger in later cycles than in the first cycle. This nonlinearity indicates that both mechanical properties of muscle and reflex mechanisms are dependent on prior movement history. We propose that this history-dependent behavior arises from the effects of prior movement on stretch reflex gain, and these effects are mediated primarily via changes in muscle spindle properties. Recordings of electromyographic activity from the FPL, during the first and second cycles of oscillation

  19. In vivo Magnetic Resonance Spectroscopy of cerebral glycogen metabolism in animals and humans.

    Science.gov (United States)

    Khowaja, Ameer; Choi, In-Young; Seaquist, Elizabeth R; Öz, Gülin

    2015-02-01

    Glycogen serves as an important energy reservoir in the human body. Despite the abundance of glycogen in the liver and skeletal muscles, its concentration in the brain is relatively low, hence its significance has been questioned. A major challenge in studying brain glycogen metabolism has been the lack of availability of non-invasive techniques for quantification of brain glycogen in vivo. Invasive methods for brain glycogen quantification such as post mortem extraction following high energy microwave irradiation are not applicable in the human brain. With the advent of (13)C Magnetic Resonance Spectroscopy (MRS), it has been possible to measure brain glycogen concentrations and turnover in physiological conditions, as well as under the influence of stressors such as hypoglycemia and visual stimulation. This review presents an overview of the principles of the (13)C MRS methodology and its applications in both animals and humans to further our understanding of glycogen metabolism under normal physiological and pathophysiological conditions such as hypoglycemia unawareness.

  20. Blood flow restriction increases metabolic stress but decreases muscle activation during high-load resistance exercise.

    Science.gov (United States)

    Teixeira, Emerson L; Barroso, Renato; Silva-Batista, Carla; Laurentino, Gilberto C; Loenneke, Jeremy P; Roschel, Hamilton; Ugrinowitsch, Carlos; Tricoli, Valmor

    2018-01-01

    We investigated differences in metabolic stress (lactate) and muscle activation (electromyography; EMG) when high-load resistance exercise (HL) is compared with a condition in which blood flow restriction (BFR) is applied during the exercise or during the rest interval. Twelve participants performed HL with BFR during the intervals (BFR-I), during the set (BFR-S), and without BFR. Each condition consisted of 3 sets of 8 repetitions with knee extension at 70% of 1-repetition maximum. Lactate and root mean square (RMS) from the surface EMG of the vastus lateralis were calculated. Lactate increased in all protocols but was higher with BFR-I than with BFR-S and HL. RMS decreased under all conditions, with a larger effect size in BFR-I (1.47) than in BFR-S (0.66) and HL (0.59). BFR-I increases lactate, possibly as a result of reduced restoration of ATP. Muscle activation seems to be impacted by mechanical stress but may be reduced by metabolic stress. Muscle Nerve 57: 107-111, 2018. © 2017 Wiley Periodicals, Inc.

  1. Muscle lactate metabolism in recovery from intense exhaustive exercise: impact of light exercise.

    Science.gov (United States)

    Bangsbo, J; Graham, T; Johansen, L; Saltin, B

    1994-10-01

    This study examined the effect of low-intensity exercise on lactate metabolism during the first 10 min of recovery from high-intensity exercise. Subjects exercised (61.0 +/- 5.4 W) one leg to exhaustion (approximately 3.5 min), and after 1 h of rest they performed the same exhaustive exercise with the other leg. For one leg the intense exercise was followed by rest [passive (P) leg], and for the other leg the exercise was followed by a 10-min period with low-intensity exercise at a work rate of 10 W [active (A) leg]. The muscle lactate concentration after the intense exercise was the same in the P and A legs, but after 10 min of recovery, the lactate concentration and the arterial blood lactate level were higher for the P leg than for the A leg (both P O2 consumption during 10 min of recovery was 440 and 750 ml for the P and A legs, respectively. The present data suggest that a lowered blood lactate level during active recovery is due to an elevated muscle lactate metabolism and is not caused by a transient higher release of lactate from the exercising muscles coupled with greater uptake in other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Nuclear receptors and epigenetic signaling: novel regulators of glycogen metabolism in skeletal muscle.

    Science.gov (United States)

    Wang, Shu-Ching Mary; Muscat, George E O

    2013-08-01

    Glycogen is an energy storage depot for the mammalian species. This review focuses on recent developments that have identified the role of nuclear hormone receptor (NR) signaling and epigenomic control in the regulation of important genes that modulate glycogen metabolism. Specifically, new studies have revealed that the NR4A subgroup (of the NR superfamily) are strikingly sensitive to beta-adrenergic stimulation in skeletal muscle, and transgenic studies in mice have revealed the expression of these NRs affects endurance and glycogen levels in muscle. Furthermore, other studies have demonstrated that one of the NR coregulator class of enzymes that mediate chromatin remodeling, the histone methyltransferases (for example, protein arginine methyltransferase 4) regulates the expression of several genes involved in glycogen metabolism and glycogen storage diseases in skeletal muscle. Importantly, NRs and histone methyltransferases, have the potential to be pharmacologically exploited and may provide novel targets in the quest to treat disorders of glycogen storage. © 2013 International Union of Biochemistry and Molecular Biology.

  3. Overexpression of PGC-1α Increases Fatty Acid Oxidative Capacity of Human Skeletal Muscle Cells

    Directory of Open Access Journals (Sweden)

    Nataša Nikolić

    2012-01-01

    Full Text Available We investigated the effects of PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α overexpression on the oxidative capacity of human skeletal muscle cells ex vivo. PGC-1α overexpression increased the oxidation rate of palmitic acid and mRNA expression of genes regulating lipid metabolism, mitochondrial biogenesis, and function in human myotubes. Basal and insulin-stimulated deoxyglucose uptake were decreased, possibly due to upregulation of PDK4 mRNA. Expression of fast fiber-type gene marker (MHCIIa was decreased. Compared to skeletal muscle in vivo, PGC-1α overexpression increased expression of several genes, which were downregulated during the process of cell isolation and culturing. In conclusion, PGC-1α overexpression increased oxidative capacity of cultured myotubes by improving lipid metabolism, increasing expression of genes involved in regulation of mitochondrial function and biogenesis, and decreasing expression of MHCIIa. These results suggest that therapies aimed at increasing PGC-1α expression may have utility in treatment of obesity and obesity-related diseases.

  4. Bionic Humans Using EAP as Artificial Muscles Reality and Challenges

    Directory of Open Access Journals (Sweden)

    Yoseph Bar-Cohen

    2008-11-01

    Full Text Available For many years, the idea of a human with bionic muscles immediately conjures up science fiction images of a TV series superhuman character that was implanted with bionic muscles and portrayed with strength and speed far superior to any normal human. As fantastic as this idea may seem, recent developments in electroactive polymers (EAP may one day make such bionics possible. Polymers that exhibit large displacement in response to stimulation that is other than electrical signal were known for many years. Initially, EAP received relatively little attention due to their limited actuation capability. However, in the recent years, the view of the EAP materials has changed due to the introduction of effective new materials that significantly surpassed the capability of the widely used piezoelectric polymer, PVDF. As this technology continues to evolve, novel mechanisms that are biologically inspired are expected to emerge. EAP materials can potentially provide actuation with lifelike response and more flexible configurations. While further improvements in performance and robustness are still needed, there already have been several reported successes. In recognition of the need for cooperation in this multidisciplinary field, the author initiated and organized a series of international forums that are leading to a growing number of research and development projects and to great advances in the field. In 1999, he challenged the worldwide science and engineering community of EAP experts to develop a robotic arm that is actuated by artificial muscles to win a wrestling match against a human opponent. In this paper, the field of EAP as artificial muscles will be reviewed covering the state of the art, the challenges and the vision for the progress in future years.

  5. Influence of aging and long-term unloading on the structure and function of human skeletal muscleThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference - Muscles as Molecular and Metabolic Machines, and has undergone the Journal's usual peer review process

    National Research Council Canada - National Science Library

    Trappe, Todd

    2009-01-01

    .... Qualitative changes that could influence the force and power producing properties of skeletal muscle are changes in the distribution of the 3 isoforms of the main motor protein myosin heavy chain (MHC...

  6. Comparison of Metabolic Network between Muscle and Intramuscular Adipose Tissues in Hanwoo Beef Cattle Using a Systems Biology Approach

    Directory of Open Access Journals (Sweden)

    Hyun-Jeong Lee

    2014-01-01

    Full Text Available The interrelationship between muscle and adipose tissues plays a major role in determining the quality of carcass traits. The objective of this study was to compare metabolic differences between muscle and intramuscular adipose (IMA tissues in the longissimus dorsi (LD of Hanwoo (Bos taurus coreanae using the RNA-seq technology and a systems biology approach. The LD sections between the 6th and 7th ribs were removed from nine (each of three cows, steers, and bulls Hanwoo beef cattle (carcass weight of 430.2±40.66 kg immediately after slaughter. The total mRNA from muscle, IMA, and subcutaneous adipose and omental adipose tissues were isolated and sequenced. The reads that passed quality control were mapped onto the bovine reference genome (build bosTau6, and differentially expressed genes across tissues were identified. The KEGG pathway enrichment tests revealed the opposite direction of metabolic regulation between muscle and IMA. Metabolic gene network analysis clearly indicated that oxidative metabolism was upregulated in muscle and downregulated in IMA. Interestingly, pathways for regulating cell adhesion, structure, and integrity and chemokine signaling pathway were upregulated in IMA and downregulated in muscle. It is thus inferred that IMA may play an important role in the regulation of development and structure of the LD tissues and muscle/adipose communication.

  7. Comparison of Metabolic Network between Muscle and Intramuscular Adipose Tissues in Hanwoo Beef Cattle Using a Systems Biology Approach.

    Science.gov (United States)

    Lee, Hyun-Jeong; Park, Hye-Sun; Kim, Woonsu; Yoon, Duhak; Seo, Seongwon

    2014-01-01

    The interrelationship between muscle and adipose tissues plays a major role in determining the quality of carcass traits. The objective of this study was to compare metabolic differences between muscle and intramuscular adipose (IMA) tissues in the longissimus dorsi (LD) of Hanwoo (Bos taurus coreanae) using the RNA-seq technology and a systems biology approach. The LD sections between the 6th and 7th ribs were removed from nine (each of three cows, steers, and bulls) Hanwoo beef cattle (carcass weight of 430.2 ± 40.66 kg) immediately after slaughter. The total mRNA from muscle, IMA, and subcutaneous adipose and omental adipose tissues were isolated and sequenced. The reads that passed quality control were mapped onto the bovine reference genome (build bosTau6), and differentially expressed genes across tissues were identified. The KEGG pathway enrichment tests revealed the opposite direction of metabolic regulation between muscle and IMA. Metabolic gene network analysis clearly indicated that oxidative metabolism was upregulated in muscle and downregulated in IMA. Interestingly, pathways for regulating cell adhesion, structure, and integrity and chemokine signaling pathway were upregulated in IMA and downregulated in muscle. It is thus inferred that IMA may play an important role in the regulation of development and structure of the LD tissues and muscle/adipose communication.

  8. Metabolic and vascular pattern in medial pterygoid muscle is altered by chronic stress in an animal model of hypodontia.

    Science.gov (United States)

    Fernández, Rodrigo Alberto Restrepo; Pereira, Yamba Carla Lara; Iyomasa, Daniela Mizusaki; Calzzani, Ricardo Alexandre; Leite-Panissi, Christie Ramos Andrade; Iyomasa, Mamie Mizusaki; Nascimento, Glauce Crivelaro

    2018-03-01

    Psychological stress is an important perpetuating, worsening and risk factor for temporomandibular disorders of muscular or articular origin. Occlusion instability, by the way, is considered a risk factor of this pathology and can be reproduced in some experimental animal models. The exact physiologic mechanism underlying these relations however, remains unclear. Our purpose was to test the hypothesis that chronic stress and unilateral exodontia induce metabolic and vascular changes in the medial pterygoid muscle of rats. Adult Wistar rats were submitted to chronic unpredictable stress and/or unilateral exodontia and their plasma and medial pterygoid muscle were removed for analysis. The parameters evaluated included plasma levels of corticosterone, metabolic activity by succinate dehydrogenase, oxidative capacity by nicotinamide adenine dinucleotide diaphorase, capillary density by laminin and alfa-CD staining and reactive oxidative species production. Chronic unpredictable stress as an isolated factor, increased oxidative metabolism, capillary density and reactive oxygen species production at medial pterygoid muscle. Conversely, exodontia has a main effect in metabolism, promoting glycolytic transformation of muscle fibers. Association of both factors induced a major glycolytic pattern in muscle and vascular changes. Our findings provide insights into the mechanisms, possibly inducing metabolic and vascular alterations on medial pterygoid muscle of rats, by which chronic stress and occlusal instabilities might be involved as risk factors in the pathophysiology of temporomandibular disorders with muscular components. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Muscle lipid metabolism in two rabbit lines divergently selected for intramuscular fat.

    Science.gov (United States)

    Martínez-Álvaro, M; Agha, S; Blasco, A; Hernández, P

    2017-06-01

    A divergent selection experiment for intramuscular fat (IMF) of LM at 9 wk of age was performed in rabbits. The objective of this work was to compare the lipid metabolism in muscles and fat tissues of the high-IMF and low-IMF lines. Lipogenic, catabolic, and lipolytic activities were studied in 2 muscles with different oxidative patterns (LM and semimembranosus proprius) and in the perirenal fat depot at 2 ages, 9 and 13 wk. In addition, adipocytes were characterized in perirenal fat. In the fifth generation, direct response to selection was 0.26 g IMF/100 g muscle. Lines showed differences in their lipogenic activities of muscles and fat tissues at 13 wk but not at 9 wk. The high-IMF line showed greater glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme (EM), and fatty acid synthase (FAS) activities in LM than the low-IMF line, with probabilities = 1.00, 0.93, and 0.90, respectively. Differences between lines were particularly great for G6PDH activity, representing 1.13 SD. The high-IMF line also showed greater G6PDH and FAS activities in semimembranosus proprius (P = 0.98 for G6PDH and 0.95 for FAS) and perirenal fat (P = 0.91 for G6PDH and 0.96 for FAS). However, in perirenal fat, EM activity was greater in the low-IMF line (P = 0.90). No differences between lines were found in almost any catabolic or lipolytic activities of muscles. Regarding adipocyte characteristics, the high-IMF line showed larger adipocytes in perirenal fat depot tissue (P = 0.97) compared to the low-IMF line, but no differences between lines were observed in the number of adipocytes. This study sheds light on the metabolic activities involved in the genetic differentiation of lipid deposition in rabbits. This study shows that lipogenic activities in muscles and fat tissues, in particular G6PDH in LM, are involved in the lipid accumulation in muscle and adipose tissues.

  10. Influence of genetic line on lipid metabolism traits of rabbit muscle.

    Science.gov (United States)

    Zomeño, C; Blasco, A; Hernández, P

    2010-10-01

    The effects of genetic line on intramuscular fat content, perirenal fat content, and activity of some enzymes involved in lipid metabolism were studied. One hundred twenty animals from 3 synthetic lines, A and V selected for litter size at weaning and R selected for growth rate between weaning and slaughter, were used in this experiment. One-half of the rabbits were slaughtered at 9 or 13 wk of age, and perirenal fat content (PF) and 2 muscles, LM and semimembranosus proprius (SP), were studied. Semimembranosus proprius muscle showed greater lipogenic [glucose-6-phosphate dehydrogenase (G6PDH) and fatty acid synthase (FAS)] and oxidative enzyme activities [β-hydroxyacyl-CoA dehydrogenase (HAD) and citrate synthase (CS)] compared with LM. Longissimus muscle had less lipogenic and more glycolytic activity (lactate dehydrogenase (LDH)] than SP. Enzymatic activity and lipid content were affected by age. Lipogenic and glycolytic enzyme activity increased from 9 to 13 wk of age in SP muscle. In LM, lipogenic activity remained stable, but glycolytic activity increased and lipolytic and oxidative activity decreased with age. Genetic line had an influence on lipogenic, lipolytic, and oxidative enzyme activities, which was related to differences in muscle lipid content (IMF). Line A showed greater lipogenic (G6PDH and malic enzyme) and lipolytic activity (neutral lipase), which was associated with a greater IMF in this line. In SP muscle, line R showed a greater HAD activity than lines A and V, and CS activity was greater in lines R and A than in line V. In LM, no differences between lines were found for oxidative enzymes. The relationship between IMF and PF was different between lines, with lines A and V showing positive correlation values (r = 0.56 and r = 0.70, respectively) and line R no relationship between both traits (r = 0.06). Results from this study showed that lipogenic and oxidative enzyme activity are related to muscle lipid deposition. Genetic line had an

  11. Elderly women with metabolic syndrome present higher cardiovascular risk and lower relative muscle strength

    Energy Technology Data Exchange (ETDEWEB)

    Farias, Darlan Lopes; Tibana, Ramires Alsamir; Teixeira, Tatiane Gomes; Vieira, Denis César Leite; Tarja, Vitor; Nascimento, Dahan da Cunha; Silva, Alessandro de Oliveira [Universidade Católica de Brasília, Brasília, DF (Brazil); Funghetto, Silvana Schwerz [Universidade de Brasília, Brasília, DF (Brazil); Coura, Maritza Alves de Sousa; Valduga, Renato [Universidade Católica de Brasília, Brasília, DF (Brazil); Karnikowski, Margô Gomes de Oliveira [Universidade de Brasília, Brasília, DF (Brazil); Prestes, Jonato [Universidade Católica de Brasília, Brasília, DF (Brazil)

    2013-07-01

    To compare the metabolic, anthropometric, arterial blood pressure, and muscle strength parameters of elderly women with and without metabolic syndrome. A case-control study with 27 (67.3±4.8 years of age, 31.0±5.0kg/m{sup 2}) elderly women with metabolic syndrome and 33 (68.8±5.6 years of age, 27.2±5.3kg/m{sup 2}) sedentary control elderly women. They were submitted to an evaluation of body composition by means of dual-energy X-ray absorptiometry and muscle strength testing with 10 maximal repetitions of knee extension. When compared to the elderly women without metabolic syndrome, those with the metabolic syndrome had higher levels for body mass (72.2±13.5 versus 63.4±14.6kg, p=0.03), body mass index (31.0±5.0 versus 27.2±5.3kg/m{sup 2,} p=0.007), fat mass (30.9±9.9 versus 24.4±8.5kg, p=0.01), systolic arterial pressure (125.1±8.2 versus 119.3±8.7mmHg, p=0.01), diastolic arterial pressure (75.5±6.9 versus 71.4±6.7mmHg, p=0.03), mean arterial pressure (92.5±6.2 versus 87.1±6.7mmHg, p=0.004), blood glucose (103.8±19.1 versus 91.1±5.9mg/dL, p=0.001), triglycerides (187.1±70.2 versus 116.3±36.7mg/dL, p=0.001), and creatine kinase (122.6±58.6 versus 89.8±32.5U/L, p=0.01); lower levels were found for fat-free mass (55.9±5.8 versus 59.3±6.7%; p=0.05), HDL-C (40.7±5.0 versus 50.5±10.1mg/dL, p=0.001), and relative muscle strength (0.53±0.14 versus 0.62±0.12, p=0.01). Elderly women with metabolic syndrome have a higher cardiovascular risk and less relative muscle strength when compared to those without metabolic syndrome. Relative muscle strength may be related to the cardiovascularr risk factors of the metabolic syndrome.

  12. Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

    Science.gov (United States)

    Coen, Paul M.; DiStefano, Giovanna; Chacon, Alexander C.; Helbling, Nicole L.; Desimone, Marisa E.; Stafanovic-Racic, Maja; Hames, Kazanna C.; Despines, Alex A.; Toledo, Frederico G. S.; Goodpaster, Bret H.

    2014-01-01

    We hypothesized that acute lipid-induced insulin resistance would be attenuated in high-oxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload. PMID:25352435

  13. The Role of miR-378a in Metabolism, Angiogenesis, and Muscle Biology

    Directory of Open Access Journals (Sweden)

    Bart Krist

    2015-01-01

    Full Text Available MicroRNA-378a (miR-378a, previously known as miR-378 is one of the small noncoding RNA molecules able to regulate gene expression at posttranscriptional level. Its two mature strands, miR-378a-3p and miR-378a-5p, originate from the first intron of the peroxisome proliferator-activated receptor gamma, coactivator 1 beta (ppargc1b gene encoding PGC-1β. Embedding in the sequence of this transcriptional regulator of oxidative energy metabolism implies involvement of miR-378a in metabolic pathways, mitochondrial energy homeostasis, and related biological processes such as muscle development, differentiation, and regeneration. On the other hand, modulating the expression of proangiogenic factors such as vascular endothelial growth factor, angiopoietin-1, or interleukin-8, influencing inflammatory reaction, and affecting tumor suppressors, such as SuFu and Fus-1, miR-378a is considered as a part of an angiogenic network in tumors. In the latter, miR-378a can evoke broader actions by enhancing cell survival, reducing apoptosis, and promoting cell migration and invasion. This review describes the current knowledge on miR-378a linking oxidative/lipid metabolism, muscle biology, and blood vessel formation.

  14. Potassium currents in cultured human pulmonary arterial smooth muscle cells.

    Science.gov (United States)

    Peng, W; Karwande, S V; Hoidal, J R; Farrukh, I S

    1996-04-01

    In this study, using whole cell and single-channel configurations of the patch-clamp technique, we characterized K+ currents (IK) in cultured human pulmonary arterial smooth muscle cells. The net whole cell outward membrane current (IKo) was activated at potentials positive to -60 mV. One component of IKo, IK(dr), was inhibited by 4-aminopyridine (4-AP) and high concentrations of tetraethylammonium (TEA) but was Ca2+ and charybdotoxin (CTX) insensitive. The other component of IKo, IK(Ca), was voltage and Ca2+ dependent and was inhibited by CTX and low concentrations of TEA. Activation of IKo in single-channel recordings was voltage dependent and demonstrated a high-conductance channel (245 +/- 2 pS) that was Ca2+ and CTX sensitive [IK(Ca)] and a low-conductance channel (109 +/- 2 pS) that was inhibited by 4-AP [IK(dr)] but was insensitive to low concentrations of TEA or to an increase in intracellular [Ca2+]. In isolated pulmonary arterial rings, TEA and 4-AP caused an additive increase in arterial tension. To our knowledge these data provide the first characterization of the IK in human pulmonary arterial smooth muscle cells and indicate that IK(Ca) and IK(dr) play an important role in maintaining pulmonary vascular tone. The data confirm previous observations in pulmonary smooth muscle cells of animal models.

  15. Thapsigargin induces apoptosis in cultured human aortic smooth muscle cells.

    Science.gov (United States)

    Peiró, C; Vallejo, S; Cercas, E; Llergo, J L; Lafuente, N; Matesanz, N; Rodríguez-Mañas, L; Sánchez-Ferrer, C F

    2000-11-01

    Vascular remodeling is a key feature of many pathologic states, including atherosclerosis, or hypertension. Vascular smooth muscle cells participate in determining the vessel structure by several mechanisms such as cell migration, cell growth, or cell death (necrosis or apoptosis). Here we report that thapsigargin, an inhibitor of endoplasmic reticulum Ca2+ -adenosine triphosphatase (ATPase), is able to induce apoptosis in human vascular smooth muscle cells (HVSMCs). Apoptosis was assessed by three different methods: differential chromatin binding dye staining. cytoplasmic histone-associated DNA fragments detection by enzyme-linked immunosorbent assay (ELISA) and terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). When HVSMCs were treated for 1 h with thapsigargin (100 nM-10 microM), there was a concentration-dependent increase in both parameters 24 h after the thapsigargin pulse. When a time-course experiment was performed, both parameters were significantly enhanced from 3 to 6 h after the exposure to thapsigargin. We conclude that thapsigargin promotes apoptosis in HVSMCs, providing a useful tool for the study of programmed cell death in human vascular smooth muscle.

  16. Calprotectin is released from human skeletal muscle tissue during exercise

    DEFF Research Database (Denmark)

    Mortensen, Ole Hartvig; Andersen, Kasper; Fischer, Christian

    2008-01-01

    at time points 0, 3 and 6 h in these individuals and in resting controls. Affymetrix microarray analysis of gene expression changes in skeletal muscle biopsies identified a small set of genes changed by IL-6 infusion. RT-PCR validation confirmed that S100A8 and S100A9 mRNA were up-regulated 3-fold...... in skeletal muscle following IL-6 infusion compared to controls. Furthermore, S100A8 and S100A9 mRNA levels were up-regulated 5-fold in human skeletal muscle following cycle ergometer exercise for 3 h at approximately 60% of in young healthy males (n = 8). S100A8 and S100A9 form calprotectin, which is known...... as an acute phase reactant. Plasma calprotectin increased 5-fold following acute cycle ergometer exercise in humans, but not following IL-6 infusion. To identify the source of calprotectin, healthy males (n = 7) performed two-legged dynamic knee extensor exercise for 3 h with a work load of approximately 50...

  17. Muscle metabolism and whole blood amino acid profile in patients with liver disease.

    Science.gov (United States)

    Dam, Gitte; Sørensen, Michael; Buhl, Mads; Sandahl, Thomas D; Møller, Niels; Ott, Peter; Vilstrup, Hendrik

    2015-01-01

    Branched-chain amino acids (BCAA) are used in liver cirrhosis to promote protein synthesis, support ammonia detoxification, and treat hepatic encephalopathy. Cirrhosis leads to subnormal BCAA plasma concentrations and studies indicate that levels are decreased due to their role in muscle ammonia removal. Muscle contribution has not been fully elucidated. We studied muscle amino acid metabolism in six healthy subjects, 13 cirrhosis patients and six patients with an episode of alcoholic hepatitis. Subjects had catheters inserted into the femoral artery and vein to obtain arterial (A) and venous (V) concentrations of amino acids (μmol/L blood). BCAA concentrations were lower in patients with cirrhosis compared to healthy subjects (p BCAA uptake was variable and on average higher in patients with alcoholic hepatitis and patients with stable cirrhosis compared to healthy subjects (mean A-V difference 0.5 and 32 vs. - 12 μmol/L blood) (p = 0.22). The release of aromatic amino acids (AAA) was comparable in the three groups (P > 0.30). The BCAA/AAA (Fischer's ratio) was lower in patients with cirrhosis and patients with alcoholic hepatitis compared to healthy subjects (mean 1.65, 1.17 and 2.73, both p BCAA and higher AAA blood concentrations compared to healthy subjects. The trend towards an increased muscle uptake of BCAA may have contributed but this was not significant.

  18. H55N polymorphism is associated with low citrate synthase activity which regulates lipid metabolism in mouse muscle cells.

    Science.gov (United States)

    Gabriel, Brendan M; Al-Tarrah, Mustafa; Alhindi, Yosra; Kilikevicius, Audrius; Venckunas, Tomas; Gray, Stuart R; Lionikas, Arimantas; Ratkevicius, Aivaras

    2017-01-01

    The H55N polymorphism in the Cs gene of A/J mice has been linked to low activity of the enzyme in skeletal muscles. The aim of the study was to test this hypothesis and examine effects of low citrate synthase (CS) activity on palmitate metabolism in muscle cells. Results of the study showed that carriers of the wild type (WT) Cs (C57BL/6J and Balb/cByJ mouse strains) had higher CS activity (p muscle. Furthermore, the recombinant CS protein of WT showed higher CS activity than the A/J variant. In C2C12 muscle cells the shRNA mediated 47% knockdown of CS activity reduced the rate of fatty acid oxidation compared to the control cells. In summary, our results are consistent with the hypothesis that H55N substitution causes a reduction in CS activity. Furthermore, low CS activity interferes with metabolic flexibility of muscle cells.

  19. The Individual, Joint, and Additive Interaction Associations of Aerobic-Based Physical Activity and Muscle Strengthening Activities on Metabolic Syndrome.

    Science.gov (United States)

    Dankel, Scott J; Loenneke, Jeremy P; Loprinzi, Paul D

    2016-12-01

    Previous research has demonstrated that physical activity and muscle strengthening activities are independently and inversely associated with metabolic syndrome. Despite a number of studies examining the individual associations, only a few studies have examined the joint associations, and to our knowledge, no previous studies have examined the potential additive interaction of performing muscle strengthening activities and aerobic-based physical activity and their association with metabolic syndrome. Using data from the 2003 to 2006 National Health and Nutrition Examination Survey (NHANES), we computed three separate multivariable logistic regression models to examine the individual, combined, and additive interaction of meeting guidelines for accelerometer-assessed physical activity and self-reported muscle strengthening activities, and their association with metabolic syndrome. We found that individuals meeting physical activity and muscle strengthening activity guidelines, respectively, were at 61 and 25 % lower odds of having metabolic syndrome. Furthermore, individuals meeting both guidelines had the lowest odds of having metabolic syndrome (70 %), in part due to the additive interaction of performing both modes of exercise. In this national sample, accelerometer-assessed physical activity and muscle strengthening activities were synergistically associated with metabolic syndrome.

  20. Immunohistochemical detection of interleukin-6 in human skeletal muscle fibers following exercise

    DEFF Research Database (Denmark)

    Penkowa, Milena; Keller, Charlotte; Keller, Pernille

    2003-01-01

    Interleukin-6 (IL-6) is produced by many different cell types. Human skeletal muscles produce and release high amounts of IL-6 during exercise; however, the cell source of origin in the muscle is not known. Therefore, we studied the protein expression of IL-6 by immunohistochemistry in human muscle...

  1. Localization and function of ATP-sensitive potassium channels in human skeletal muscle

    DEFF Research Database (Denmark)

    Nielsen, Jens Jung; Kristensen, Michael; Hellsten, Ylva

    2003-01-01

    The present study investigated the localization of ATP-sensitive K+ (KATP) channels in human skeletal muscle and the functional importance of these channels for human muscle K+ distribution at rest and during muscle activity. Membrane fractionation based on the giant vesicle technique...

  2. Passive heat acclimation improves skeletal muscle contractility in humans.

    Science.gov (United States)

    Racinais, S; Wilson, M G; Périard, J D

    2017-01-01

    The aim of this study was to investigate the effect of repeated passive heat exposure (i.e., acclimation) on muscle contractility in humans. Fourteen nonheat-acclimated males completed two trials including electrically evoked twitches and voluntary contractions in thermoneutral conditions [Cool: 24°C, 40% relative humidity (RH)] and hot ambient conditions in the hyperthermic state (Hot: 44-50°C, 50% RH) on consecutive days in a counterbalanced order. Rectal temperature was ~36.5°C in Cool and was maintained at ~39°C throughout Hot. Both trials were repeated after 11 days of passive heat acclimation (1 h per day, 48-50°C, 50% RH). Heat acclimation decreased core temperature in Cool (-0.2°C, P rate in Hot (+0.7 liter/h, P heat acclimation improved skeletal muscle contractility as evidenced by an increase in evoked peak twitch amplitude both in Cool (20.5 ± 3.6 vs. 22.0 ± 4.0 N·m) and Hot (20.5 ± 4.7 vs. 22.0 ± 4.0 N·m) (+9%, P heat acclimation improves skeletal muscle contractile function during electrically evoked and voluntary muscle contractions of different intensities both in Cool and Hot. These results suggest that repeated heat exposure may have important implications to passively maintain or even improve muscle function in a variety of performance and clinical settings. Copyright © 2017 the American Physiological Society.

  3. Four-week cold acclimation in adult humans shifts uncoupling thermogenesis from skeletal muscles to brown adipose tissue.

    Science.gov (United States)

    Blondin, Denis P; Daoud, Amani; Taylor, Taryn; Tingelstad, Hans C; Bézaire, Véronic; Richard, Denis; Carpentier, André C; Taylor, Albert W; Harper, Mary-Ellen; Aguer, Céline; Haman, François

    2017-03-15

    Muscle-derived thermogenesis during acute cold exposure in humans consists of a combination of cold-induced increases in skeletal muscle proton leak and shivering. Daily cold exposure results in an increase in brown adipose tissue oxidative capacity coupled with a decrease in the cold-induced skeletal muscle proton leak and shivering intensity. Improved coupling between electromyography-determined muscle activity and whole-body heat production following cold acclimation suggests a maintenance of ATPase-dependent thermogenesis and decrease in skeletal muscle ATPase independent thermogenesis. Although daily cold exposure did not change the fibre composition of the vastus lateralis, the fibre composition was a strong predictor of the shivering pattern evoked during acute cold exposure. We previously showed that 4 weeks of daily cold exposure in humans can increase brown adipose tissue (BAT) volume by 45% and oxidative metabolism by 182%. Surprisingly, we did not find a reciprocal reduction in shivering intensity when exposed to a mild cold (18°C). The present study aimed to determine whether changes in skeletal muscle oxidative metabolism or shivering activity could account for these unexpected findings. Nine men participated in a 4 week cold acclimation intervention (10°C water circulating in liquid-conditioned suit, 2 h day-1 , 5 days week-1 ). Shivering intensity and pattern were measured continuously during controlled cold exposure (150 min at 4 °C) before and after the acclimation. Muscle biopsies from the m. vastus lateralis were obtained to measure oxygen consumption rate and proton leak of permeabilized muscle fibres. Cold acclimation elicited a modest 21% (P pattern evoked during acute cold. We conclude that muscle-derived thermogenesis during acute cold exposure in humans is not only limited to shivering, but also includes cold-induced increases in proton leak. The efficiency of muscle oxidative phosphorylation improves with cold acclimation

  4. Systems biology from micro-organisms to human metabolic diseases: the role of detailed kinetic models.

    Science.gov (United States)

    Bakker, Barbara M; van Eunen, Karen; Jeneson, Jeroen A L; van Riel, Natal A W; Bruggeman, Frank J; Teusink, Bas

    2010-10-01

    Human metabolic diseases are typically network diseases. This holds not only for multifactorial diseases, such as metabolic syndrome or Type 2 diabetes, but even when a single gene defect is the primary cause, where the adaptive response of the entire network determines the severity of disease. The latter may differ between individuals carrying the same mutation. Understanding the adaptive responses of human metabolism naturally requires a systems biology approach. Modelling of metabolic pathways in micro-organisms and some mammalian tissues has yielded many insights, qualitative as well as quantitative, into their control and regulation. Yet, even for a well-known pathway such as glycolysis, precise predictions of metabolite dynamics from experimentally determined enzyme kinetics have been only moderately successful. In the present review, we compare kinetic models of glycolysis in three cell types (African trypanosomes, yeast and skeletal muscle), evaluate their predictive power and identify limitations in our understanding. Although each of these models has its own merits and shortcomings, they also share common features. For example, in each case independently measured enzyme kinetic parameters were used as input. Based on these 'lessons from glycolysis', we will discuss how to make best use of kinetic computer models to advance our understanding of human metabolic diseases.

  5. Muscle spindle composition and distribution in human young masseter and biceps brachii muscles reveal early growth and maturation.

    Science.gov (United States)

    Osterlund, Catharina; Liu, Jing-Xia; Thornell, Lars-Eric; Eriksson, Per-Olof

    2011-04-01

    Significant changes in extrafusal fiber type composition take place in the human masseter muscle from young age, 3-7 years, to adulthood, in parallel with jaw-face skeleton growth, changes of dentitions and improvement of jaw functions. As motor and sensory control systems of muscles are interlinked, also the intrafusal fiber population, that is, muscle spindles, should undergo age-related changes in fiber type appearance. To test this hypothesis, we examined muscle spindles in the young masseter muscle and compared the result with previous data on adult masseter spindles. Also muscle spindles in the young biceps brachii muscle were examined. The result showed that muscle spindle composition and distribution were alike in young and adult masseter. As for the adult masseter, young masseter contained exceptionally large muscle spindles, and with the highest spindle density and most complex spindles found in the deep masseter portion. Hence, contrary to our hypothesis, masseter spindles do not undergo major morphological changes between young age and adulthood. Also in the biceps, young spindles were alike adult spindles. Taken together, the results showed that human masseter and biceps muscle spindles are morphologically mature already at young age. We conclude that muscle spindles in the human young masseter and biceps precede the extrafusal fiber population in growth and maturation. This in turn suggests early reflex control and proprioceptive demands in learning and maturation of jaw motor skills. Similarly, well-developed muscle spindles in young biceps reflect early need of reflex control in learning and performing arm motor behavior. Copyright © 2011 Wiley-Liss, Inc.

  6. Effects of menopause and high-intensity training on insulin sensitivity and muscle metabolism

    DEFF Research Database (Denmark)

    Mandrup, Camilla M; Egelund, Jon; Nyberg, Michael

    2018-01-01

    To investigate peripheral insulin sensitivity and skeletal muscle glucose metabolism in premenopausal and postmenopausal women, and evaluate whether exercise training benefits are maintained after menopause. Sedentary, healthy, normal-weight, late premenopausal (n = 21), and early postmenopausal (n...... = 20) women were included in a 3-month high-intensity exercise training intervention. Body composition was assessed by magnetic resonance imaging and dual-energy x-ray absorptiometry, whole body glucose disposal rate (GDR) by hyperinsulinemic euglycemic clamp (40 mU/m/min), and femoral muscle glucose....... Training increased lean body mass (estimate [95% confidence interval] 0.5 [0.2-0.9] kg, P ...

  7. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III.

    Science.gov (United States)

    Preisler, Nicolai; Laforêt, Pascal; Madsen, Karen Lindhardt; Prahm, Kira Philipsen; Hedermann, Gitte; Vissing, Christoffer Rasmus; Galbo, Henrik; Vissing, John

    2015-04-28

    Glycogen storage disease type IIIa (GSDIIIa) is classically regarded as a glycogenosis with fixed weakness, but we hypothesized that exercise intolerance in GSDIIIa is related to muscle energy failure and that oral fructose ingestion could improve exercise tolerance in this metabolic myopathy. We challenged metabolism with cycle-ergometer exercise and measured substrate turnover and oxidation rates using stable isotope methodology and indirect calorimetry in 3 patients and 6 age-matched controls on 1 day, and examined the effect of fructose ingestion on exercise tolerance in the patients on another day. Total fatty acid oxidation rates during exercise were higher in patients than controls, 32.1 (SE 1.2) vs 20.7 (SE 0.5; range 15.8-29.3) μmol/kg/min (p = 0.048), and oxidation of carbohydrates was lower in patients, 1.0 (SE 5.4) vs 38.4 (SE 8.0; range 23.0-77.1) μmol/kg/min (p = 0.024). Fructose ingestion improved exercise tolerance in the patients. Similar to patients with McArdle disease, in whom muscle glycogenolysis is also impaired, GSDIIIa is associated with a reduced skeletal muscle oxidation of carbohydrates and a compensatory increase in fatty acid oxidation, and fructose ingestion improves exercise tolerance. Our results indicate that GSDIIIa should not only be viewed as a glycogenosis with fixed skeletal muscle weakness, but should also be considered among the glycogenoses presenting with exercise-related dynamic symptoms caused by muscular energy deficiency. This study provides Class IV evidence that ingestion of fructose improves exercise tolerance in patients with GSDIIIa. © 2015 American Academy of Neurology.

  8. Metabolic Effects of Insulin and IGFs on Gilthead Sea Bream (Sparus aurata) Muscle Cells

    Science.gov (United States)

    Montserrat, Núria; Capilla, Encarnación; Navarro, Isabel; Gutiérrez, Joaquim

    2012-01-01

    Primary cultures of gilthead sea bream myocytes were performed in order to examine the relative metabolic function of insulin compared with IGF-I and IGF-II (insulin-like growth factors, IGFs) at different stages in the cell culture. In these cells, the in vitro effects of insulin and IGFs on 2-deoxyglucose (2-DG) and l-alanine uptake were studied in both myocytes (day 4) and small myotubes (day 9). 2-DG uptake in gilthead sea bream muscle cells was increased in the presence of insulin and IGFs in a time dependent manner and along with muscle cell differentiation. On the contrary, l-alanine uptake was also stimulated by insulin and IGFs but showed an inverse pattern, being the uptake higher in small myocytes than in large myotubes. The results of preincubation with inhibitors (PD-98059, wortmannin, and cytochalasin B) on 2-DG uptake indicated that insulin and IGFs stimulate glucose uptake through the same mechanisms, and evidenced that mitogenesis activator protein kinase (MAPK) and PI3K–Akt transduction pathways mediate the metabolic function of these peptides. In the same way, we observed that GLUT4 protein synthesis was stimulated in the presence of insulin and IGFs in gilthead sea bream muscle cells in a different manner at days 4 or 9 of the culture. In summary we describe here, for the first time, the effects of insulin and IGFs on 2-DG and l-alanine uptake in primary culture of gilthead sea bream muscle cells. We show that both MAPK and PI3K–Akt transduction pathways are needed in order to control insulin and IGFs actions in these cells. Moreover, changes in glucose uptake can be explained by the action of the GLUT4 transporter, which is stimulated in the presence of insulin and IGFs throughout the cell culture. PMID:22654873

  9. Clonal characterization of rat muscle satellite cells: proliferation, metabolism and differentiation define an intrinsic heterogeneity.

    Directory of Open Access Journals (Sweden)

    Carlo A Rossi

    2010-01-01

    Full Text Available Satellite cells (SCs represent a distinct lineage of myogenic progenitors responsible for the postnatal growth, repair and maintenance of skeletal muscle. Distinguished on the basis of their unique position in mature skeletal muscle, SCs were considered unipotent stem cells with the ability of generating a unique specialized phenotype. Subsequently, it was demonstrated in mice that opposite differentiation towards osteogenic and adipogenic pathways was also possible. Even though the pool of SCs is accepted as the major, and possibly the only, source of myonuclei in postnatal muscle, it is likely that SCs are not all multipotent stem cells and evidences for diversities within the myogenic compartment have been described both in vitro and in vivo. Here, by isolating single fibers from rat flexor digitorum brevis (FDB muscle we were able to identify and clonally characterize two main subpopulations of SCs: the low proliferative clones (LPC present in major proportion (approximately 75% and the high proliferative clones (HPC, present instead in minor amount (approximately 25%. LPC spontaneously generate myotubes whilst HPC differentiate into adipocytes even though they may skip the adipogenic program if co-cultured with LPC. LPC and HPC differ also for mitochondrial membrane potential (DeltaPsi(m, ATP balance and Reactive Oxygen Species (ROS generation underlying diversities in metabolism that precede differentiation. Notably, SCs heterogeneity is retained in vivo. SCs may therefore be comprised of two distinct, though not irreversibly committed, populations of cells distinguishable for prominent differences in basal biological features such as proliferation, metabolism and differentiation. By these means, novel insights on SCs heterogeneity are provided and evidences for biological readouts potentially relevant for diagnostic purposes described.

  10. Role of the kidney in human leptin metabolism

    National Research Council Canada - National Science Library

    Christian Meyer; Dave Robson; Noya Rackovsky; Veena Nadkarni; John Gerich

    1997-01-01

    To assess the role of the human kidney in leptin metabolism, we measured renal leptin net balance and urinary leptin excretion in 16 normal postabsorptive volunteers with varying degrees of obesity...

  11. Longitudinal Changes in Glucose Metabolism of Denervated Muscle after Complete Peripheral Nerve Injury.

    Science.gov (United States)

    Pak, Kyoungjune; Shin, Myung Jun; Hwang, Sung-Jun; Shin, Jin-Hong; Shin, Hwa Kyoung; Kim, Seong Jang; Kim, In Joo

    2016-10-01

    Electrodiagnostic studies can obtain information 2 or 3 weeks after an acute nerve injury. Previous studies have shown increased glucose metabolism in denervated muscles 1 week after injury using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomography (PET). Therefore, this study aimed to evaluate the changes in glucose metabolism in denervated muscles using serial monitoring by [(18)F]FDG PET scans. Denervation was induced in eight male Sprague-Dawley rats (aged 7 weeks old) weighing 200-250 g. The right legs of the rats were denervated by resecting the sciatic nerve in the thigh after the initial skin incision. Two rats were sacrificed 1 and 10 weeks after denervation. Skeletal muscles (gastrocnemius and tibialis anterior) were excised from both the right and left legs of the rats. Staining with hematoxylin and eosin, glucose transporter (GLUT)-1, GLUT-4, and hexokinase II was undertaken. PET/computed tomography (CT) scans were performed on the six remaining rats a total of five times at 1, 2, 5, 8, and 10 weeks after denervation. Regions of interest were drawn on integrated PET/CT images to measure the degree of [(18)F]FDG uptake in the right and left lower leg muscles. Target-to-background ratios (TBRs) were calculated by dividing the FDG uptake of the lower leg muscles by that of the upper leg muscles. The TBRs of the denervated muscles were higher than those of the control muscles at both 1 (6.84 ± 1.98 vs. 1.18 ± 0.11, p = 0.009) and 2 (4.10 ± 2.05 vs. 1.86 ± 0.73, p = 0.0374) weeks after denervation. After 5 (2.18 ± 0.78 vs. 1.35 ± 0.47, p = 0.1489), 8 (1.76 ± 0.18 vs. 1.69 ± 0.18, p = 0.5127), and 10 (1.76 ± 0.52 vs. 1.56 ± 0.37, p = 0.5637) weeks, the difference in the TBRs between the denervated and controls became non-significant. [(18)F]FDG PET can visualize increased glucose metabolism in a denervated muscle early as 1 week after injury. Therefore, PET

  12. A compendium of inborn errors of metabolism mapped onto the human metabolic network.

    OpenAIRE

    Sahoo, Swagatika; Franzson, Leifur; Jonsson, Jon J; Thiele, Ines

    2012-01-01

    Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn Inborn errors of metabolism (IEMs) are hereditary metabolic defects, which are encountered in almost all major metabolic pathways occurring in man. Many IEMs are screened for in neonates through metabolomic analysis of dried blood spot samples. To enable the mapping of these metabolomic data onto the published human metabolic reconstruction, we added missing reactions and pathways involved in acylcarnitin...

  13. Exercise with weight loss improves adipose tissue and skeletal muscle markers of fatty acid metabolism in postmenopausal women.

    Science.gov (United States)

    Ortmeyer, Heidi K; Goldberg, Andrew P; Ryan, Alice S

    2017-07-01

    The effects of 6-month weight loss (WL) versus aerobic exercise training (AEX)+WL on fat and skeletal muscle markers of fatty acid metabolism were determined in normal (NGT) and impaired (IGT) glucose tolerant African-American and Caucasian postmenopausal women with overweight/obesity. Fat (gluteal and abdominal) lipoprotein lipase (LPL), skeletal muscle LPL, acyl-CoA synthase (ACS), ß-hydroxacyl-CoA dehydrogenase, carnitine palmitoyltransferase (CPT-1), and citrate synthase (CS) activities were measured at baseline (n = 104) and before and after WL (n = 34) and AEX+WL (n = 37). After controlling for age and race, muscle LPL and CPT-1 were lower in IGT, and the ratios of fat/muscle LPL activity were higher in IGT compared to NGT. Muscle LPL was related to insulin sensitivity (M value) and inversely related to G120 , fasting insulin, and homeostatic model assessment of insulin resistance. AEX+WL decreased abdominal fat LPL and increased muscle LPL, ACS, and CS. The ratios of fat/muscle LPL decreased after AEX+WL. The change in VO2 max was related to the changes in LPL, ACS, and CS and inversely related to the changes in fat/muscle LPL activity ratios. Six-month AEX+WL, and not WL alone, is capable of enhancing skeletal muscle fatty acid metabolism in postmenopausal African-American and Caucasian women with NGT, IGT, and overweight/obesity. © 2017 The Obesity Society.

  14. Distinct Skeletal Muscle Gene Regulation from Active Contraction, Passive Vibration, and Whole Body Heat Stress in Humans.

    Directory of Open Access Journals (Sweden)

    Michael A Petrie

    Full Text Available Skeletal muscle exercise regulates several important metabolic genes in humans. We know little about the effects of environmental stress (heat and mechanical stress (vibration on skeletal muscle. Passive mechanical stress or systemic heat stress are often used in combination with many active exercise programs. We designed a method to deliver a vibration stress and systemic heat stress to compare the effects with active skeletal muscle contraction.The purpose of this study is to examine whether active mechanical stress (muscle contraction, passive mechanical stress (vibration, or systemic whole body heat stress regulates key gene signatures associated with muscle metabolism, hypertrophy/atrophy, and inflammation/repair.Eleven subjects, six able-bodied and five with chronic spinal cord injury (SCI participated in the study. The six able-bodied subjects sat in a heat stress chamber for 30 minutes. Five subjects with SCI received a single dose of limb-segment vibration or a dose of repetitive electrically induced muscle contractions. Three hours after the completion of each stress, we performed a muscle biopsy (vastus lateralis or soleus to analyze mRNA gene expression.We discovered repetitive active muscle contractions up regulated metabolic transcription factors NR4A3 (12.45 fold, PGC-1α (5.46 fold, and ABRA (5.98 fold; and repressed MSTN (0.56 fold. Heat stress repressed PGC-1α (0.74 fold change; p < 0.05; while vibration induced FOXK2 (2.36 fold change; p < 0.05. Vibration similarly caused a down regulation of MSTN (0.74 fold change; p < 0.05, but to a lesser extent than active muscle contraction. Vibration induced FOXK2 (p < 0.05 while heat stress repressed PGC-1α (0.74 fold and ANKRD1 genes (0.51 fold; p < 0.05.These findings support a distinct gene regulation in response to heat stress, vibration, and muscle contractions. Understanding these responses may assist in developing regenerative rehabilitation interventions to improve muscle cell

  15. Skeletal Muscle Derived IL-6 in Liver and Adipose Tissue Metabolism

    DEFF Research Database (Denmark)

    Knudsen, Jakob Grunnet

    was to investigate the effect of exercise on key factors in liver glucose and fat metabolism. This study demonstrated that PDH and ACC phosphorylation was decreased and that changes in hepatic PEPCK and G6Pase protein content does not contribute to gluconeogenesis during 1h of exercise in mice. These findings...... indicate that during 1h of exercise the liver utilizes carbohydrates for oxidation rather than gluconeogenesis and that gluconeogenic activity during 1h of exercise is not regulated through increases in protein content. The aim of study III was to investigate the role of skeletal muscle derived IL-6...

  16. Metabolic adaptations of skeletal muscle to voluntary wheel running exercise in hypertensive heart failure rats

    DEFF Research Database (Denmark)

    Schultz, R L; Kullman, E L; Waters, Ryan

    2013-01-01

    The Spontaneously Hypertensive Heart Failure (SHHF) rat mimics the human progression of hypertension from hypertrophy to heart failure. However, it is unknown whether SHHF animals can exercise at sufficient levels to observe beneficial biochemical adaptations in skeletal muscle. Thirty-seven female...... and expression, and glycogen utilization. The SHHFex rats ran a greater distance and duration as compared to the WFex rats (PSkeletal muscle citrate synthase and beta-hydroxyacyl-CoA dehydrogenase enzyme activity was not altered in the SHHFex group...... robust amounts of aerobic activity, voluntary wheel running exercise was not sufficiently intense to improve the oxidative capacity of skeletal muscle in adult SHHF animals, indicating an inability to compensate for declining heart function by improving peripheral oxidative adaptations in the skeletal...

  17. Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins

    Energy Technology Data Exchange (ETDEWEB)

    Sirvent, P., E-mail: pascal.sirvent@univ-bpclermont.fr [U1046, INSERM, Université Montpellier 1 and Université Montpellier 2, 34295 Montpellier (France); CHRU Montpellier, 34295 Montpellier (France); Clermont Université, Université Blaise Pascal, EA 3533, Laboratoire des Adaptations Métaboliques à l' Exercice en conditions Physiologiques et Pathologiques (AME2P), BP 80026, F-63171 Aubière cedex (France); Fabre, O.; Bordenave, S. [U1046, INSERM, Université Montpellier 1 and Université Montpellier 2, 34295 Montpellier (France); CHRU Montpellier, 34295 Montpellier (France); Hillaire-Buys, D. [CHRU Montpellier, 34295 Montpellier (France); Raynaud De Mauverger, E.; Lacampagne, A.; Mercier, J. [U1046, INSERM, Université Montpellier 1 and Université Montpellier 2, 34295 Montpellier (France); CHRU Montpellier, 34295 Montpellier (France)

    2012-03-01

    The most common and problematic side effect of statins is myopathy. To date, the patho-physiological mechanisms of statin myotoxicity are still not clearly understood. In previous studies, we showed that acute application in vitro of simvastatin caused impairment of mitochondrial function and dysfunction of calcium homeostasis in human and rat healthy muscle samples. We thus evaluated in the present study, mitochondrial function and calcium signaling in muscles of patients treated with statins, who present or not muscle symptoms, by oxygraphy and recording of calcium sparks, respectively. Patients treated with statins showed impairment of mitochondrial respiration that involved mainly the complex I of the respiratory chain and altered frequency and amplitude of calcium sparks. The muscle problems observed in statin-treated patients appear thus to be related to impairment of mitochondrial function and muscle calcium homeostasis, confirming the results we previously reported in vitro. -- Highlights: ► The most common and problematic side effect of statins is myopathy. ► Patients treated with statins showed impairment of mitochondrial respiration. ► Statins-treated patients showed altered frequency and amplitude of calcium sparks.

  18. Exercise, Amino Acids and Aging in the Control of Human Muscle Protein Synthesis

    Science.gov (United States)

    Walker, Dillon K.; Dickinson, Jared M.; Timmerman, Kyle L.; Drummond, Micah J.; Reidy, Paul T.; Fry, Christopher S.; Gundermann, David M.; Rasmussen, Blake B.

    2012-01-01

    In this review we discuss recent research in the field of human skeletal muscle protein metabolism characterizing the acute regulation of mammalian target of rapamycin complex (mTORC) 1 signaling and muscle protein synthesis (MPS) by exercise, amino acid nutrition and aging. Resistance exercise performed in the fasted state stimulates mixed MPS within 1 h post-exercise, which can remain elevated for 48 h. We demonstrate that the activation of mTORC1 signaling (and subsequently enhanced translation initiation) is required for the contraction-induced increase in MPS. In comparison, low-intensity blood flow restriction (BFR) exercise stimulates MPS and mTORC1 signaling to an extent similar to traditional, high-intensity resistance exercise. We also show that mTORC1 signaling is required for the essential amino acid (EAA) induced increase in MPS. Ingestion of EAAs (or protein) shortly following resistance exercise enhances MPS and mTORC1 signaling as compared to resistance exercise or EAAs alone. In older adults, the ability of skeletal muscle to respond to anabolic stimuli is impaired. For example, in response to an acute bout of resistance exercise, older adults are less able to activate mTORC1 or increase MPS during the first 24h of post-exercise recovery. However, BFR exercise can overcome this impairment. Aging is not associated with a reduced response to EAAs provided the EAA content is sufficient. Therefore, we propose that exercise combined with EAA should be effective not only in improving muscle repair and growth in response to training in athletes, but that strategies such as EAA combined with resistance exercise (or BFR exercise) may be very useful as a countermeasure for sarcopenia and other clinical conditions associated with muscle wasting. PMID:21606874

  19. Effect of nutritional factors on biochemical, structural and metabolic characteristics of muscles in ruminants, consequences on dietetic value and sensorial qualities of meat.

    Science.gov (United States)

    Geay, Y; Bauchart, D; Hocquette, J F; Culioli, J

    2001-01-01

    Ruminant meat is an important source of nutrients and is also of high sensory value. However, the importance and nature of these characteristics depend on ruminant nutrition. The first part of this review is focused on biochemical and dietetic value of this meat. It offers a panel of quantitative and qualitative contributions, especially through its fatty acids characteristics. Since saturated and trans-monounsaturated fatty acids are considered as harmful to human health, their amount in muscles can be reduced by increasing the proportions of dietary polyunsaturated fatty acids (PUFA) absorbed by the animals. On the contrary, some fatty acids (n-6 and n-3 PUFA, conjugated linoleic acid) specifically incorporated in muscle tissues would play a favourable role in the prevention or reduction of major diseases in human (cancers, atherosclerosis, obesity) and therefore be recommended. The second part of this review treats different aspects of the sensorial qualities of meat. Skeletal muscle structure and its biochemical components influence muscle transformation to meat and sensorial qualities including tenderness, colour, flavour and juiciness. This paper shows how nutrition can influence, in ruminants, metabolic activity as well as muscle structure and composition, and thereby affect meat quality.

  20. Enantioselective gas chromatographic separation of methylsulfonyl PCBs in seal blubber, pelican muscle and human adipose tissues

    Energy Technology Data Exchange (ETDEWEB)

    Karasek, L.; Rosmus, J. [Veterinary Institute Prague (Czech Republic). Dept. of Chemistry; Hajslova, J. [Institute of Chemical Technology (Czech Republic). Dept. of Food Chemistry and Analysis; Huehnerfuss, H. [Hamburg Univ. (Germany). Inst. fuer Organische Chemie

    2004-09-15

    Methyl sulfone derivatives are known to represent primary metabolic products of PCBs (MeSO2- CB) and DDE (MeSO2-DDE). These metabolites are formed via mercapturic acid pathway and belong to persistent, lipophilic compounds which accumulate in the adipose, lung, liver and kidney tissues of mammals exposed to PCBs. In 1976 Jenssen and Jansson reported the identification of PCB methyl sulfones as metabolites of PCBs in Baltic grey seal blubber. Methyl sulfones are moderately polar compounds that are only slightly less hydrophobic than the parent PCBs, and their partition coefficients fulfill the requirements for bioaccumulation. The highest concentrations have been found in kidney and lung tissues of seals, otters, beluga whales, polar bears, fishes and in human tissues. In the present investigation two samples of seal blubber, two pelican muscles and eleven human adipose tissue samples were analysed with regard to their concentrations of PCB parent compounds as well as to the respective chiral methylsulfonyl metabolites.

  1. Skeletal Muscle Remodeling in Response to Eccentric vs. Concentric Loading: Morphological, Molecular, and Metabolic Adaptations

    Directory of Open Access Journals (Sweden)

    Martino V. Franchi

    2017-07-01

    Full Text Available Skeletal muscle contracts either by shortening or lengthening (concentrically or eccentrically, respectively; however, the two contractions substantially differ from one another in terms of mechanisms of force generation, maximum force production and energy cost. It is generally known that eccentric actions generate greater force than isometric and concentric contractions and at a lower metabolic cost. Hence, by virtue of the greater mechanical loading involved in active lengthening, eccentric resistance training (ECC RT is assumed to produce greater hypertrophy than concentric resistance training (CON RT. Nonetheless, prevalence of either ECC RT or CON RT in inducing gains in muscle mass is still an open issue, with some studies reporting greater hypertrophy with eccentric, some with concentric and some with similar hypertrophy within both training modes. Recent observations suggest that such hypertrophic responses to lengthening vs. shortening contractions are achieved by different adaptations in muscle architecture. Whilst the changes in muscle protein synthesis in response to acute and chronic concentric and eccentric exercise bouts seem very similar, the molecular mechanisms regulating the myogenic adaptations to the two distinct loading stimuli are still incompletely understood.Thus, the present review aims to, (a critically discuss the literature on the contribution of eccentric vs. concentric loading to muscular hypertrophy and structural remodeling, and, (b clarify the molecular mechanisms that may regulate such adaptations.We conclude that, when matched for either maximum load or work, similar increase in muscle size is found between ECC and CON RT. However, such hypertrophic changes appear to be achieved through distinct structural adaptations, which may be regulated by different myogenic and molecular responses observed between lengthening and shortening contractions.

  2. Noninvasive PET Imaging and Tracking of Engineered Human Muscle Precursor Cells for Skeletal Muscle Tissue Engineering.

    Science.gov (United States)

    Haralampieva, Deana; Betzel, Thomas; Dinulovic, Ivana; Salemi, Souzan; Stoelting, Meline; Krämer, Stefanie D; Schibli, Roger; Sulser, Tullio; Handschin, Christoph; Eberli, Daniel; Ametamey, Simon M

    2016-09-01

    Transplantation of human muscle precursor cells (hMPCs) is envisioned for the treatment of various muscle diseases. However, a feasible noninvasive tool to monitor cell survival, migration, and integration into the host tissue is still missing. In this study, we designed an adenoviral delivery system to genetically modify hMPCs to express a signaling-deficient form of human dopamine D2 receptor (hD2R). The gene expression levels of the receptor were evaluated by reverse transcriptase polymerase chain reaction, and infection efficiency was evaluated by fluorescent microscopy. The viability, proliferation, and differentiation capacity of the transduced cells, as well as their myogenic phenotype, were determined by flow cytometry analysis and fluorescent microscopy. (18)F-fallypride and (18)F-fluoromisonidazole, two well-established PET radioligands, were assessed for their potential to image engineered hMPCs in a mouse model and their uptakes were evaluated at different time points after cell inoculation in vivo. Biodistribution studies, autoradiography, and PET experiments were performed to determine the extent of signal specificity. To address feasibility for tracking hMPCs in an in vivo model, the safety of the adenoviral gene delivery was evaluated. Finally, the harvested tissues were histologically examined to determine whether survival of the transplanted cells was sustained at different time points. Adenoviral gene delivery was shown to be safe, with no detrimental effects on the primary human cells. The viability, proliferation, and differentiation capacity of the transduced cells were confirmed, and flow cytometry analysis and fluorescent microscopy showed that their myogenic phenotype was sustained. (18)F-fallypride and (18)F-fluoromisonidazole were successfully synthesized. Specific binding of (18)F-fallypride to hD2R hMPCs was demonstrated in vitro and in vivo. Furthermore, the (18)F-fluoromisonidazole signal was high at the early stages. Finally

  3. Metabolic selection of glycosylation defects in human cells

    Energy Technology Data Exchange (ETDEWEB)

    Yarema, Kevin J.; Goon, Scarlett; Bertozzi, Carolyn R.

    2000-08-01

    Changes in glycosylation are often associated with disease progression, but the genetic and metabolic basis of these events is rarely understood in detail at a molecular level. This report describes a novel metabolism-based approach to the selection of mutants in glycoconjugate biosynthesis that has provided insight into regulatory mechanisms for oligosaccharide expression and metabolic flux. Unnatural intermediates are used to challenge a specific pathway and cell-surface expression of their metabolic products provides a readout of flux in that pathway and a basis for selecting genetic mutants. The approach was applied to the sialic acid metabolic pathway in human cells, yielding novel mutants with phenotypes related to the inborn metabolic defect sialuria and metastatic tumor cells.

  4. Ginsenoside Rb1 improves energy metabolism in the skeletal muscle of an animal model of postoperative fatigue syndrome.

    Science.gov (United States)

    Tan, Shan-Jun; Li, Ning; Zhou, Feng; Dong, Qian-Tong; Zhang, Xiao-Dong; Chen, Bi-Cheng; Yu, Zhen

    2014-10-01

    Postoperative fatigue syndrome (POFS) is a common clinical complication followed by almost every major abdominal surgery. Ginsenoside Rb1 (GRb1), a principle ginsenoside in ginseng, could exert a potent anti-fatigue effect on POFS. However, the mechanism is still unknown. Previous studies revealed that alterations in the energy metabolism in the skeletal muscle may play a vital role in the development and progression of fatigue. In the present study, we investigate the effect of GRb1 on energy metabolism in the skeletal muscle of a rat model of POFS induced by major small intestinal resection. GRb1 (10 mg/kg) was intraperitoneally administrated once daily for 1, 3, 7, and 10 d from the operation day, respectively. The locomotor activity was recorded every day, and total food intake was calculated starting from 24 h after surgery. After GRb1 treatment was completed, blood and skeletal muscle were sampled. The level of blood glucose was determined by an automatic biochemical analyzer. The content of adenosine triphosphate (ATP) in skeletal muscle was determined by high-performance liquid chromatography. The activity of energy metabolic enzymes Na(+)-K(+)-ATPase, pyruvate kinase, and succinate dehydrogenase (SDH) was assessed by commercially available kits. The results revealed that GRb1 could increase locomotor activity of POFS rats and significantly increase their total food intake postoperatively (P muscle of POFS rats (P muscle of POFS rats was enhanced by GRb1 (P 0.05). These results suggest that GRb1 may improve skeletal muscle energy metabolism in POFS, and the underlying mechanism may be associated with an increase in the content of ATP and an enhancement in the activity of energy metabolic enzymes such as Na(+)-K(+)-ATPase ATPase and SDH in the skeletal muscle. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Homeostatic effects of exercise and sleep on metabolic processes in mice with an overexpressed skeletal muscle clock.

    Science.gov (United States)

    Brager, Allison J; Heemstra, Lydia; Bhambra, Raman; Ehlen, J Christopher; Esser, Karyn A; Paul, Ketema N; Novak, Colleen M

    2017-01-01

    Brain and muscle-ARNT-like factor (Bmal1/BMAL1) is an essential transcriptional/translational factor of circadian clocks. Loss of function of Bmal1/BMAL1 is highly disruptive to physiological and behavioral processes. In light of these previous findings, we examined if transgenic overexpression of Bmal1/BMAL1 in skeletal muscle could alter metabolic processes. First, we characterized in vivo and ex vivo metabolic phenotypes of muscle overexpressed mice (male and female) compared to wild-type littermates (WT). Second, we examined in vivo and ex vivo metabolic processes in the presence of positive and negative homeostatic challenges: high-intensity treadmill running (positive) and acute sleep deprivation (negative). In vivo measures of metabolic processes included body composition, respiratory exchange ratio (RER; VCO2/VO2), energy expenditure, total activity counts, and food intake collected from small animal indirect calorimetry. Ex vivo measure of insulin sensitivity in skeletal muscle was determined from radioassays. RER was lower for muscle overexpressed females compared to female WTs. There were no genotype-dependent differences in metabolic phenotypes for males. With homeostatic challenges, muscle overexpressed mice had lower energy expenditure after high-intensity treadmill running. Acute sleep deprivation reduced insulin sensitivity in skeletal muscle in overexpressed male mice, but not male WTs. The present study contributes to a body of evidence showing pleiotropic, non-circadian, and homeostatic effects of altered Bmal1/BMAL1 expression on metabolic processes, demonstrating a critical need to further investigate the broad and complex actions of Bmal1/BMAL1 on physiology and behavior. Published by Elsevier B.V.

  6. Modelling human myoblasts survival upon xenotransplantation into immunodeficient mouse muscle.

    Science.gov (United States)

    Praud, Christophe; Vauchez, Karine; Zongo, Pascal; Vilquin, Jean-Thomas

    2018-03-15

    Cell transplantation has been challenged in several clinical indications of genetic or acquired muscular diseases, but therapeutic success were mitigated. To understand and improve the yields of tissue regeneration, we aimed at modelling the fate of CD56-positive human myoblasts after transplantation. Using immunodeficient severe combined immunodeficiency (SCID) mice as recipients, we assessed the survival, integration and satellite cell niche occupancy of human myoblasts by a triple immunohistochemical labelling of laminin, dystrophin and human lamin A/C. The counts were integrated into a classical mathematical decline equation. After injection, human cells were essentially located in the endomysium, then they disappeared progressively from D0 to D28. The final number of integrated human nuclei was grossly determined at D2 after injection, suggesting that no more efficient fusion between donor myoblasts and host fibers occurs after the resolution of the local damages created by needle insertion. Almost 1% of implanted human cells occupied a satellite-like cell niche. Our mathematical model validated by histological counting provided a reliable quantitative estimate of human myoblast survival and/or incorporation into SCID muscle fibers. Informations brought by histological labelling and this mathematical model are complementary. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Experimental model of human corpus cavernosum smooth muscle relaxation

    Directory of Open Access Journals (Sweden)

    Rommel P. Regadas

    2010-08-01

    Full Text Available PURPOSE: To describe a technique for en bloc harvesting of the corpus cavernosum, cavernous artery and urethra from transplant organ donors and contraction-relaxation experiments with corpus cavernosum smooth muscle. MATERIALS AND METHODS: The corpus cavernosum was dissected to the point of attachment with the crus penis. A 3 cm segment (corpus cavernosum and urethra was isolated and placed in ice-cold sterile transportation buffer. Under magnification, the cavernous artery was dissected. Thus, 2 cm fragments of cavernous artery and corpus cavernosum were obtained. Strips measuring 3 x 3 x 8 mm3 were then mounted vertically in an isolated organ bath device. Contractions were measured isometrically with a Narco-Biosystems force displacement transducer (model F-60, Narco-Biosystems, Houston, TX, USA and recorded on a 4-channel Narco-Biosystems desk model polygraph. RESULTS: Phenylephrine (1µM was used to induce tonic contractions in the corpus cavernosum (3 - 5 g tension and cavernous artery (0.5 - 1g tension until reaching a plateau. After precontraction, smooth muscle relaxants were used to produce relaxation-response curves (10-12M to 10-4 M. Sodium nitroprusside was used as a relaxation control. CONCLUSION: The harvesting technique and the smooth muscle contraction-relaxation model described in this study were shown to be useful instruments in the search for new drugs for the treatment of human erectile dysfunction.

  8. Experimental model of human corpus cavernosum smooth muscle relaxation.

    Science.gov (United States)

    Regadas, Rommel P; Moraes, Maria E A; Mesquita, Francisco J C; Cerqueira, Joao B G; Gonzaga-Silva, Lucio F

    2010-01-01

    To describe a technique for en bloc harvesting of the corpus cavernosum, cavernous artery and urethra from transplant organ donors and contraction-relaxation experiments with corpus cavernosum smooth muscle. The corpus cavernosum was dissected to the point of attachment with the crus penis. A 3 cm segment (corpus cavernosum and urethra) was isolated and placed in ice-cold sterile transportation buffer. Under magnification, the cavernous artery was dissected. Thus, 2 cm fragments of cavernous artery and corpus cavernosum were obtained. Strips measuring 3 x 3 x 8 mm(3) were then mounted vertically in an isolated organ bath device. Contractions were measured isometrically with a Narco-Biosystems force displacement transducer (model F-60, Narco-Biosystems, Houston, TX, USA) and recorded on a 4-channel Narco-Biosystems desk model polygraph. Phenylephrine (1 microM) was used to induce tonic contractions in the corpus cavernosum (3-5 g tension) and cavernous artery (0.5-1 g tension) until reaching a plateau. After precontraction, smooth muscle relaxants were used to produce relaxation-response curves (10(-12) M to 10(-4) M). Sodium nitroprusside was used as a relaxation control. The harvesting technique and the smooth muscle contraction-relaxation model described in this study were shown to be useful instruments in the search for new drugs for the treatment of human erectile dysfunction.

  9. Muscle Fatigue Affects the Interpolated Twitch Technique When Assessed Using Electrically-Induced Contractions in Human and Rat Muscles.

    Science.gov (United States)

    Neyroud, Daria; Cheng, Arthur J; Bourdillon, Nicolas; Kayser, Bengt; Place, Nicolas; Westerblad, Håkan

    2016-01-01

    The interpolated twitch technique (ITT) is the gold standard to assess voluntary activation and central fatigue. Yet, its validity has been questioned. Here we studied how peripheral fatigue can affect the ITT. Repeated contractions at submaximal frequencies were produced by supramaximal electrical stimulations of the human adductor pollicis muscle in vivo and of isolated rat soleus fiber bundles; an extra stimulation pulse was given during contractions to induce a superimposed twitch. Human muscles fatigued by repeated 30-Hz stimulation trains (3 s on-1 s off) showed an ~80% reduction in the superimposed twitch force accompanied by a severely reduced EMG response (M-wave amplitude), which implies action potential failure. Subsequent experiments combined a less intense stimulation protocol (1.5 s on-3 s off) with ischemia to cause muscle fatigue, but which preserved M-wave amplitude. However, the superimposed twitch force still decreased markedly more than the potentiated twitch force; with ITT this would reflect increased "voluntary activation." In contrast, the superimposed twitch force was relatively spared when a similar protocol was performed in rat soleus bundles. Force relaxation was slowed by >150% in fatigued human muscles, whereas it was unchanged in rat soleus bundles. Accordingly, results similar to those in the human muscle were obtained when relaxation was slowed by cooling the rat soleus muscles. In conclusion, our data demonstrate that muscle fatigue can confound the quantification of central fatigue using the ITT.

  10. AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle.

    Science.gov (United States)

    de Laat, M A; Robinson, M A; Gruntmeir, K J; Liu, Y; Soma, L R; Lacombe, V A

    2015-09-01

    Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P managing IR requires investigation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Contralateral muscle activity and fatigue in the human first dorsal interosseous muscle

    NARCIS (Netherlands)

    Post, Marijn; Bayrak, Sibel; Kernell, Daniel; Zijdewind, Inge

    During effortful unilateral contractions, muscle activation is not limited to the target muscles but activity is also observed in contralateral muscles. The amount of this associated activity is depressed in a fatigued muscle, even after correction for fatigue-related changes in maximal force. In

  12. Partitioning the metabolic cost of human running: a task-by-task approach.

    Science.gov (United States)

    Arellano, Christopher J; Kram, Rodger

    2014-12-01

    Compared with other species, humans can be very tractable and thus an ideal "model system" for investigating the metabolic cost of locomotion. Here, we review the biomechanical basis for the metabolic cost of running. Running has been historically modeled as a simple spring-mass system whereby the leg acts as a linear spring, storing, and returning elastic potential energy during stance. However, if running can be modeled as a simple spring-mass system with the underlying assumption of perfect elastic energy storage and return, why does running incur a metabolic cost at all? In 1980, Taylor et al. proposed the "cost of generating force" hypothesis, which was based on the idea that elastic structures allow the muscles to transform metabolic energy into force, and not necessarily mechanical work. In 1990, Kram and Taylor then provided a more explicit and quantitative explanation by demonstrating that the rate of metabolic energy consumption is proportional to body weight and inversely proportional to the time of foot-ground contact for a variety of animals ranging in size and running speed. With a focus on humans, Kram and his colleagues then adopted a task-by-task approach and initially found that the metabolic cost of running could be "individually" partitioned into body weight support (74%), propulsion (37%), and leg-swing (20%). Summing all these biomechanical tasks leads to a paradoxical overestimation of 131%. To further elucidate the possible interactions between these tasks, later studies quantified the reductions in metabolic cost in response to synergistic combinations of body weight support, aiding horizontal forces, and leg-swing-assist forces. This synergistic approach revealed that the interactive nature of body weight support and forward propulsion comprises ∼80% of the net metabolic cost of running. The task of leg-swing at most comprises ∼7% of the net metabolic cost of running and is independent of body weight support and forward propulsion. In

  13. Lactate dehydrogenase is not a mitochondrial enzyme in human and mouse vastus lateralis muscle

    Science.gov (United States)

    Rasmussen, Hans N; van Hall, Gerrit; Rasmussen, Ulla F

    2002-01-01

    The presence of lactate dehydrogenase in skeletal muscle mitochondria was investigated to clarify whether lactate is a possible substrate for mitochondrial respiration. Mitochondria were prepared from 100 mg samples of human and mouse vastus lateralis muscle. All fractions from the preparation procedure were assayed for marker enzymes and lactate dehydrogenase (LDH). The mitochondrial fraction contained no LDH activity (detection limit ∼0.05 % of the tissue activity) and the distribution of LDH activity among the fractions paralleled that of pyruvate kinase, i.e. LDH was fractionated as a cytoplasmic enzyme. Respiratory experiments with the mitochondrial fraction also indicated the absence of LDH. Lactate did not cause respiration, nor did it affect the respiration of pyruvate + malate. The major part of the native cytochrome c was retained in the isolated mitochondria, which, furthermore, showed high specific rates of state 3 respiration. This excluded artificial loss from the mitochondria of all activity of a possible LDH. It was concluded that skeletal muscle mitochondria are devoid of LDH and unable to metabolize lactate. PMID:12042361

  14. Sarcoglycan and integrin localization in normal human skeletal muscle: a confocal laser scanning microscope study

    Directory of Open Access Journals (Sweden)

    G Anastasi

    2009-06-01

    Full Text Available Many studies have been performed on the sarcoglycan subcomplex and a7B and b1D integrins, but their distribution and localization patterns along the non-junctional sarcolemma are still not clear. We have carried out an indirect immunofluorescence study on surgical biopsies of normal human skeletal muscle, performing double localization reactions with antibodies to sarcoglycans, integrins and sarcomeric actin. Our results indicate that the tested proteins colocalize with each other. In a few cases, a-sarcoglycan does not colocalize with the other sarcoglycans and integrins. We also demonstrated, by employing antibodies to all the tested proteins, that these proteins can be localized to regions of the sarcolemma corresponding either to the I-band or Aband. Our results seem to confirm the hypothesis of a correlation between the region of the sarcolemma occupied by costameric proteins and the metabolic type (fast or slow of muscle fibers. On this basis, we suggest that slow fibers are characterized by localization of costameric proteins to Ibands, while fast fibers are characterized by localization of costameric proteins to A-bands. The results open a new line of research in understanding interactions between the components of the DGC and vinculin-talin-integrin complexes in the context of different fiber types. Moreover, the same results may be extended to skeletal muscle fibers affected by neuromuscular diseases to detect possible structural alterations.

  15. Sarcoglycan and integrin localization in normal human skeletal muscle: a confocal laser scanning microscope study.

    Science.gov (United States)

    Anastasi, G; Cutroneo, G; Rizzo, G; Arco, A; Santoro, G; Bramanti, P; Vitetta, A G; Pisani, A; Trimarchi, F; Favaloro, A

    2004-01-01

    Many studies have been performed on the sarcoglycan sub-complex and a7B and b1D integrins, but their distribution and localization patterns along the non-junctional sarcolemma are still not clear. We have carried out an indirect immunofluorescence study on surgical biopsies of normal human skeletal muscle, performing double localization reactions with antibodies to sarcoglycans, integrins and sarcomeric actin. Our results indicate that the tested proteins colocalize with each other. In a few cases, a-sarcoglycan does not colocalize with the other sarcoglycans and integrins. We also demonstrated, by employing antibodies to all the tested proteins, that these proteins can be localized to regions of the sarcolemma corresponding either to the I-band or A-band. Our results seem to confirm the hypothesis of a correlation between the region of the sarcolemma occupied by costameric proteins and the metabolic type (fast or slow) of muscle fibers. On this basis, we suggest that slow fibers are characterized by localization of costameric proteins to I-bands, while fast fibers are characterized by localization of costameric proteins to A-bands. The results open a new line of research in understanding interactions between the components of the DGC and vinculin-talin-integrin complexes in the context of different fiber types. Moreover, the same results may be extended to skeletal muscle fibers affected by neuromuscular diseases to detect possible structural alterations.

  16. Influence of creatine supplementation on indicators of glucose metabolism in skeletal muscle of exercised rats

    Directory of Open Access Journals (Sweden)

    Michel Barbosa de Araújo

    2013-12-01

    Full Text Available The purpose of this study was to evaluate the effect of creatine supplementation in the diet on indicators of glucose metabolism in skeletal muscle of exercised rats. Forty Wistar adult rats were distributed into four groups for eight weeks: 1 Control: sedentary rats that received balanced diet; 2 Creatine control: sedentary rats that received supplementation of 2% creatine in the balanced diet; 3 Trained: rats that ran on a treadmill at the Maximal Lactate Steady State and received balanced diet; and 4 Supplemented-trained: rats that ran on a treadmill at the Maximal Lactate Steady State and received creatine supplementation (2% in the balanced diet. The hydric intake increased and the body weight gain decreased in the supplemented-trained group. In the soleus muscle, the glucose oxidation increased in both supplemented groups. The production of lactate and glycemia during glucose tolerance test decreased in the supplemented-trained group. Creatine supplementation in conjunction with exercise training improved muscular glycidic metabolism of rats.

  17. Paternal reproductive strategy influences metabolic capacities and muscle development of Atlantic salmon (Salmo salar L.) embryos.

    Science.gov (United States)

    Morasse, Sébastien; Guderley, Helga; Dodson, Julian J

    2008-01-01

    Male Atlantic salmon follow a conditional strategy, becoming either "combatants" that undertake a seaward migration and spend at least a year at sea or "sneakers" that remain in freshwater and mature as parr. A variety of physiological indices showed significant but small differences between the offspring of males that use these two reproductive tactics. Offspring fathered by anadromous male Atlantic salmon (Salmo salar L.) showed greater muscular development and muscle metabolic capacities but lower spontaneous movements than those fathered by mature male parr. At hatch and at maximum attainable wet weight (MAWW), offspring fathered by anadromous males had higher activities of mitochondrial (cytochrome C oxidase and citrate synthase) and glycolytic (lactate dehydrogenase [LDH]) enzymes than progeny of mature male parr. Enzymatic profiles of progeny of anadromous fathers also suggested greater nitrogen excretion capacity (glutamate dehydrogenase) and increased muscular development (creatine kinase and LDH) than in the progeny of mature parr. At MAWW, juveniles fathered by mature parr made considerably more spontaneous movements, presumably increasing their energy expenditures. For juveniles fathered by anadromous males, total cross-sectional areas of white and red muscle at hatch were higher due to the greater number of large-diameter fibers. We suggest that the slightly lower metabolic capacities and muscular development of alevins fathered by mature parr could reflect differences in energy partitioning during their dependence on vitellus. Greater spontaneous movements of offspring of mature male parr could favor feeding and growth after the resorption of the vitellus.

  18. Phenotypic and metabolic features of mouse diaphragm and gastrocnemius muscles in chronic lung carcinogenesis: influence of underlying emphysema.

    Science.gov (United States)

    Salazar-Degracia, Anna; Blanco, David; Vilà-Ubach, Mònica; de Biurrun, Gabriel; de Solórzano, Carlos Ortiz; Montuenga, Luis M; Barreiro, Esther

    2016-08-23

    Muscle wasting negatively impacts the progress of chronic diseases such as lung cancer (LC) and emphysema, which are in turn interrelated. We hypothesized that muscle atrophy and body weight loss may develop in an experimental mouse model of lung carcinogenesis, that the profile of alterations in muscle fiber phenotype (fiber type composition and morphometry, muscle structural alterations, and nuclear apoptosis), and in muscle metabolism are similar in both respiratory and limb muscles of the tumor-bearing mice, and that the presence of underlying emphysema may influence those events. Diaphragm and gastrocnemius muscles of mice with urethane-induced lung cancer (LC-U) with and without elastase-induced emphysema (E-U) and non-exposed controls (N = 8/group) were studied: fiber type composition, morphometry, muscle abnormalities, apoptotic nuclei (immunohistochemistry), and proteolytic and autophagy markers (immunoblotting) at 20- and 35-week exposure times. In the latter cohort, structural contractile proteins, creatine kinase (CK), peroxisome proliferator-activated receptor (PPAR) expression, oxidative stress, and inflammation were also measured. Body and muscle weights were quantified (baseline, during follow-up, and sacrifice). Compared to controls, in U and E-U mice, whole body, diaphragm and gastrocnemius weights were reduced. Additionally, both in diaphragm and gastrocnemius, muscle fiber cross-sectional areas were smaller, structural abnormalities, autophagy and apoptotic nuclei were increased, while levels of actin, myosin, CK, PPARs, and antioxidants were decreased, and muscle proteolytic markers did not vary among groups. In this model of lung carcinogenesis with and without emphysema, reduced body weight gain and muscle atrophy were observed in respiratory and limb muscles of mice after 20- and 35-week exposure times most likely through increased nuclear apoptosis and autophagy. Underlying emphysema induced a larger reduction in the size of slow- and

  19. Role of protein farnesylation in burn-induced metabolic derangements and insulin resistance in mouse skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Harumasa Nakazawa

    Full Text Available OBJECTIVE: Metabolic derangements, including insulin resistance and hyperlactatemia, are a major complication of major trauma (e.g., burn injury and affect the prognosis of burn patients. Protein farnesylation, a posttranslational lipid modification of cysteine residues, has been emerging as a potential component of inflammatory response in sepsis. However, farnesylation has not yet been studied in major trauma. To study a role of farnesylation in burn-induced metabolic aberration, we examined the effects of farnesyltransferase (FTase inhibitor, FTI-277, on burn-induced insulin resistance and metabolic alterations in mouse skeletal muscle. METHODS: A full thickness burn (30% total body surface area was produced under anesthesia in male C57BL/6 mice at 8 weeks of age. After the mice were treated with FTI-277 (5 mg/kg/day, IP or vehicle for 3 days, muscle insulin signaling, metabolic alterations and inflammatory gene expression were evaluated. RESULTS: Burn increased FTase expression and farnesylated proteins in mouse muscle compared with sham-burn at 3 days after burn. Simultaneously, insulin-stimulated phosphorylation of insulin receptor (IR, insulin receptor substrate (IRS-1, Akt and GSK-3β was decreased. Protein expression of PTP-1B (a negative regulator of IR-IRS-1 signaling, PTEN (a negative regulator of Akt-mediated signaling, protein degradation and lactate release by muscle, and plasma lactate levels were increased by burn. Burn-induced impaired insulin signaling and metabolic dysfunction were associated with increased inflammatory gene expression. These burn-induced alterations were reversed or ameliorated by FTI-277. CONCLUSIONS: Our data demonstrate that burn increased FTase expression and protein farnesylation along with insulin resistance, metabolic alterations and inflammatory response in mouse skeletal muscle, all of which were prevented by FTI-277 treatment. These results indicate that increased protein farnesylation plays a

  20. Decreased functional capacity and muscle strength in elderly women with metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Vieira DCL

    2013-10-01

    Full Text Available Denis Cesar Leite Vieira,1 Ramires Alsamir Tibana,1 Vitor Tajra,1 Dahan da Cunha Nascimento,1 Darlan Lopes de Farias,1 Alessandro de Oliveira Silva,1 Tatiane Gomes Teixeira,1 Romulo Maia Carlos Fonseca,2 Ricardo Jacó de Oliveira,2 Felipe Augusto dos Santos Mendes,2 Wagner Rodrigues Martins,2 Silvana Schwerz Funghetto,2 Margo Gomes de Oliveira Karnikowski,2 James Wilfred Navalta,3 Jonato Prestes11Graduate Program on Physical Education, Catholic University of Brasilia, Brasilia, Brazil; 2University of Brasilia, UnB, Brasilia, Brazil; 3Department of Kinesiology and Nutrition Sciences of the University of Nevada, Las Vegas, NV, USAPurpose: To compare the metabolic parameters, flexibility, muscle strength, functional capacity, and lower limb muscle power of elderly women with and without the metabolic syndrome (MetS.Methods: This cross-sectional study included 28 older women divided into two groups: with the MetS (n = 14; 67.3 ± 5.5 years; 67.5 ± 16.7 kg; 1.45 ± 0.35 m; 28.0 ± 7.6 kg/m2, and without the MetS (n = 14; 68.7 ± 5.3 years; 58.2 ± 9.9 kg; 1.55 ± 0.10 m; 24.3 ± 3.8 kg/m2. Body composition was evaluated by dual-energy X-ray absorptiometry and dynamic muscle strength was assessed by one-maximum repetition (1RM tests in leg press, bench press and biceps curl exercises. Six-minute walk test, Timed Up and Go (TUG; 30-second sitting-rising; arm curl using a 2-kg dumbbell, sit-and-reach (flexibility, and vertical jump tests were performed.Results: There was no difference between groups regarding age (P = 0.49, height (P = 0.46, body fat (% (P = 0.19, systolic (P = 0.64, diastolic (P = 0.41 and mean blood pressure (P = 0.86, 30-second sitting-rising (P = 0.57, 30-s arm curl (P = 0.73, leg press 1RM (P = 0.51, bench press 1RM (P = 0.77, and biceps curl 1RM (P = 0.85. However, women without the MetS presented lower body mass (P = 0.001, body mass index (BMI (P = 0.0001, waist circumference (P = 0.02, waist-to-height ratio (P = 0.02, fat body

  1. Investigation of biomarkers alterations after an acute tissue trauma in human trapezius muscle, using microdialysis

    DEFF Research Database (Denmark)

    Sørensen, Line Bay; Gazerani, Parisa; Wåhlén, Karin

    2018-01-01

    Alterations in muscle milieu are suggested as important activity of peripheral drive in patients with chronic musculoskeletal pain (CMP). Microdialysis (MD) has been used in monitoring altered metabolic response pattern in muscles. However, the insertion of MD probe causes a local tissue trauma. ...

  2. Differential Muscle Involvement in Mice and Humans Affected by McArdle Disease

    DEFF Research Database (Denmark)

    Krag, Thomas O; Pinós, Tomàs; Nielsen, Tue L

    2016-01-01

    McArdle disease (muscle glycogenosis type V) is caused by myophosphorylase deficiency, which leads to impaired glycogen breakdown. We investigated how myophosphorylase deficiency affects muscle physiology, morphology, and glucose metabolism in 20-week-old McArdle mice and compared the findings to...

  3. Co-expression Network Approach Reveals Functional Similarities among Diseases Affecting Human Skeletal Muscle

    OpenAIRE

    Kavitha Mukund; Shankar Subramaniam

    2017-01-01

    Diseases affecting skeletal muscle exhibit considerable heterogeneity in intensity, etiology, phenotypic manifestation and gene expression. Systems biology approaches using network theory, allows for a holistic understanding of functional similarities amongst diseases. Here we propose a co-expression based, network theoretic approach to extract functional similarities from 20 heterogeneous diseases comprising of dystrophinopathies, inflammatory myopathies, neuromuscular, and muscle metabolic ...

  4. Alpine Skiing With total knee ArthroPlasty (ASWAP): metabolism, inflammation, and skeletal muscle fiber characteristics.

    Science.gov (United States)

    Kristensen, M; Pötzelsberger, B; Scheiber, P; Bergdahl, A; Hansen, C N; Andersen, J L; Narici, M; Salvioli, S; Conte, M; Müller, E; Dela, F

    2015-08-01

    We investigated the effect of alpine skiing for 12 weeks on skeletal muscle characteristics and biomarkers of glucose homeostasis and cardiovascular risk factors. Twenty-three patients with a total knee arthroplasty (TKA) were studied 2.9 ± 0.9 years (mean ± SD) after the operation. Fourteen patients participated in the intervention group (IG) and nine in the control group (CG). Blood samples and muscle biopsies were obtained before (PRE) and 7.3 ± 0.8 days after (POST) the intervention, and blood samples again after a retention (RET) phase of 8 weeks. With skiing, glucose homeostasis improved in IG (decrease in fasting insulin, increase in muscle glycogen) but not in CG. Fiber type distribution and size, as well as capillary density and number of capillaries around the fibers (CAF), were not different between the operated and the non-operated leg in either group. The relative number of type I fibers increased with skiing in IG with no change in CG. Inflammatory biomarkers, plasma lipids, and mitochondrial proteins and activity did not change. Alpine skiing is metabolically beneficial and can be used as a training modality by elderly people with TKA. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Angiotensin-(1-7) recruits muscle microvasculature and enhances insulin's metabolic action via mas receptor.

    Science.gov (United States)

    Fu, Zhuo; Zhao, Lina; Aylor, Kevin W; Carey, Robert M; Barrett, Eugene J; Liu, Zhenqi

    2014-06-01

    Angiotensin-(1-7) [Ang-(1-7)], an endogenous ligand for the G protein-coupled receptor Mas, exerts both vasodilatory and insulin-sensitizing effects. In skeletal muscle, relaxation of precapillary arterioles recruits microvasculature and increases the endothelial surface area available for nutrient and hormone exchanges. To assess whether Ang-(1-7) recruits microvasculature and enhances insulin action in muscle, overnight-fasted adult rats received an intravenous infusion of Ang-(1-7) (0, 10, or 100 ng/kg per minute) for 150 minutes with or without a simultaneous infusion of the Mas inhibitor A-779 and a superimposition of a euglycemic insulin clamp (3 mU/kg per minute) from 30 to 150 minutes. Hind limb muscle microvascular blood volume, microvascular flow velocity, and microvascular blood flow were determined. Myographic changes in tension were measured on preconstricted distal saphenous artery. Ang-(1-7) dose-dependently relaxed the saphenous artery (Pmicrovasculature and enhances the metabolic action of insulin. These effects may contribute to the cardiovascular protective responses associated with Mas activation and explain the insulin-sensitizing action of Ang-(1-7).

  6. Effects of dietary energy sources on early postmortem muscle metabolism of finishing pigs.

    Science.gov (United States)

    Li, Yanjiao; Yu, Changning; Li, Jiaolong; Zhang, Lin; Gao, Feng; Zhou, Guanghong

    2017-12-01

    This study investigated the effects of different dietary energy sources on early postmortem muscle metabolism of finishing pigs. Seventy-two barrow (Duroc×Landrace×Yorkshire, DLY) pigs (65.0±2.0 kg) were allotted to three iso-energetic and iso-nitrogenous diets: A (44.1% starch, 5.9% crude fat, and 12.6% neutral detergent fibre [NDF]), B (37.6% starch, 9.5% crude fat, and 15.4% NDF) or C (30.9% starch, 14.3% crude fat, and 17.8% NDF). After the duration of 28-day feeding experiment, 24 pigs (eight per treatment) were slaughtered and the M. longissimus lumborum (LL) samples at 45 min postmortem were collected. Compared with diet A, diet C resulted in greater adenosine triphosphate and decreased phosphocreatine (PCr) concentrations, greater activity of creatine kinase and reduced percentage bound activities of hexokinase (HK), and pyruvate kinase (PK) in LL muscles (p<0.05). Moreover, diet C decreased the phosphor-AKT level and increased the hydroxy-hypoxia-inducible factor-1α (HIF-1α) level, as well as decreased the bound protein expressions of HK II, PKM2, and lactate dehydrogenase A (p<0.05). Diet C with the lowest level of starch and the highest levels of fat and NDF could enhance the PCr utilization and attenuate glycolysis early postmortem in LL muscle of finishing pigs.

  7. Metabolic demands and replenishment of muscle glycogen after a rugby league match simulation protocol.

    Science.gov (United States)

    Bradley, Warren J; Hannon, Marcus P; Benford, Victoria; Morehen, James C; Twist, Craig; Shepherd, Sam; Cocks, Matthew; Impey, Samuel G; Cooper, Robert G; Morton, James P; Close, Graeme L

    2017-09-01

    The metabolic requirements of a rugby league match simulation protocol and the timing of carbohydrate provision on glycogen re-synthesis in damaged muscle were examined. Fifteen (mean±SD: age 20.9±2.9 year, body-mass 87.3±14.1kg, height 177.4±6.0cm) rugby league (RL) players consumed a 6gkgday-1 CHO diet for 7-days, completed a time to exhaustion test (TTE) and a glycogen depletion protocol on day-3, a RL simulated-match protocol (RLMSP) on day-5 and a TTE on day-7. Players were prescribed an immediate or delayed (2-h-post) re-feed post-simulation. Muscle biopsies and blood samples were obtained post-depletion, before and after simulated match-play, and 48-h after match-play with PlayerLoad and heart-rate collected throughout the simulation. Data were analysed using effects sizes±90% CI and magnitude-based inferences. PlayerLoad (8.0±0.7 AUmin-1) and %HRpeak (83±4.9%) during the simulation were similar to values reported for RL match-play. Muscle glycogen very likely increased from immediately after to 48-h post-simulation (272±97 cf. 416±162mmolkg-1d.w.; ES±90%CI) after immediate re-feed, but changes were unclear (283±68 cf. 361±144mmolkg-1d.w.; ES±90%CI) after delayed re-feed. CK almost certainly increased by 77.9±25.4% (0.75±0.19) post-simulation for all players. The RLMSP presents a replication of the internal loads associated with professional RL match-play, although difficulties in replicating the collision reduced the metabolic demands and glycogen utilisation. Further, it is possible to replete muscle glycogen in damaged muscle employing an immediate re-feed strategy. Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  8. Systematic analysis of adaptations in aerobic capacity and submaximal energy metabolism provides a unique insight into determinants of human aerobic performance

    DEFF Research Database (Denmark)

    Vollaard, Niels B J; Constantin-Teodosiu, Dimitru; Fredriksson, Katarina

    2009-01-01

    It has not been established which physiological processes contribute to endurance training-related changes (Delta) in aerobic performance. For example, the relationship between intramuscular metabolic responses at the intensity used during training and improved human functional capacity has...... Deltalactate (r(2) = 0.32; P humans are not related to altered maximal oxygen transport capacity. Altered muscle metabolism may provide the link between training...

  9. Rapid determination of myosin heavy chain expression in rat, mouse, and human skeletal muscle using multicolor immunofluorescence analysis.

    Directory of Open Access Journals (Sweden)

    Darin Bloemberg

    Full Text Available Skeletal muscle is a heterogeneous tissue comprised of fibers with different morphological, functional, and metabolic properties. Different muscles contain varying proportions of fiber types; therefore, accurate identification is important. A number of histochemical methods are used to determine muscle fiber type; however, these techniques have several disadvantages. Immunofluorescence analysis is a sensitive method that allows for simultaneous evaluation of multiple MHC isoforms on a large number of fibers on a single cross-section, and offers a more precise means of identifying fiber types. In this investigation we characterized pure and hybrid fiber type distribution in 10 rat and 10 mouse skeletal muscles, as well as human vastus lateralis (VL using multicolor immunofluorescence analysis. In addition, we determined fiber type-specific cross-sectional area (CSA, succinate dehydrogenase (SDH activity, and α-glycerophosphate dehydrogenase (GPD activity. Using this procedure we were able to easily identify pure and hybrid fiber populations in rat, mouse, and human muscle. Hybrid fibers were identified in all species and made up a significant portion of the total population in some rat and mouse muscles. For example, rat mixed gastrocnemius (MG contained 12.2% hybrid fibers whereas mouse white tibialis anterior (WTA contained 12.1% hybrid fibers. Collectively, we outline a simple and time-efficient method for determining MHC expression in skeletal muscle of multiple species. In addition, we provide a useful resource of the pure and hybrid fiber type distribution, fiber CSA, and relative fiber type-specific SDH and GPD activity in a number of rat and mouse muscles.

  10. Pharmacokinetics and metabolism of rosaramicin in humans.

    Science.gov (United States)

    Lin, C C; Chung, M; Gural, R; Schuessler, D; Kim, H K; Radwanski, E; Marco, A; DiGiore, C; Symchowicz, S

    1984-01-01

    The pharmacokinetics of rosaramicin was studied in subjects receiving 500 mg of the drug (i) by 1-h intravenous infusion, (ii) in solution orally, or (iii) as tablets orally. After intravenous administration, the rosaramicin levels in serum declined rapidly with t1/2S of 0.27 h for the distribution phase and 3.28 h for the elimination phase. The apparent volume of distribution was 3.78 liter/kg, and the total body clearance was 13.41 ml/min per kg, indicating extensive tissue distribution or metabolism or both. Similar pharmacokinetic data were obtained after oral administration of the drug in solution or tablets and after intravenous dosing. The absolute bioavailability of the drug administered orally, in either tablets or solution, was 32 to 39%. The metabolism and excretion of [14C]rosaramicin administered orally were also evaluated in volunteers. The serum area under the curve (infinity) of unchanged rosaramicin was 19% of that of total radioactivity, indicating extensive metabolism of the drug. About 7.0% of the radioactivity was recovered in the urine, and 86.7% was recovered in the feces. Only a small amount of unchanged rosaramicin was present in the urine (7 to 9% of urinary radioactivity), but none was present in the feces. The major metabolite, 20-bis-ureidorosaramicin, represented 17 to 38% of the radioactivity in the urine and 26 to 29% of the radioactivity in the feces. PMID:6517543

  11. Dietary protein intake affects expression of genes for lipid metabolism in porcine skeletal muscle in a genotype-dependent manner.

    Science.gov (United States)

    Liu, Yingying; Li, Fengna; He, Lingyun; Tan, Bie; Deng, Jinping; Kong, Xiangfeng; Li, Yinghui; Geng, Meimei; Yin, Yulong; Wu, Guoyao

    2015-04-14

    Skeletal muscle is a major site for the oxidation of fatty acids (FA) in mammals, including humans. Using a swine model, we tested the hypothesis that dietary protein intake regulates the expression of key genes for lipid metabolism in skeletal muscle. A total of ninety-six barrows (forty-eight pure-bred Bama mini-pigs (fatty genotype) and forty-eight Landrace pigs (lean genotype)) were fed from 5 weeks of age to market weight. Pigs of fatty or lean genotype were randomly assigned to one of two dietary treatments (low- or adequate-protein diet), with twenty-four individually fed pigs per treatment. Our data showed that dietary protein levels affected the expression of genes involved in the anabolism and catabolism of lipids in the longissimus dorsi and biceps femoris muscles in a genotype-dependent manner. Specifically, Bama mini-pigs had more intramuscular fat, SFA and MUFA, as well as elevated mRNA expression levels of lipogenic genes, compared with Landrace pigs. In contrast, Bama mini-pigs had lower mRNA expression levels of lipolytic genes than Landrace pigs fed an adequate-protein diet in the growing phase. These data are consistent with higher white-fat deposition in Bama mini-pigs than in Landrace pigs. In conclusion, adequate provision of dietary protein (amino acids) plays an important role in regulating the expression of key lipogenic genes, and the growth of white adipose tissue, in a genotype- and tissue-specific manner. These findings have important implications for developing novel dietary strategies in pig production.

  12. Effects of lubiprostone on human uterine smooth muscle cells.

    Science.gov (United States)

    Cuppoletti, John; Malinowska, Danuta H; Chakrabarti, Jayati; Ueno, Ryuji

    2008-06-01

    Lubiprostone, a bicyclic fatty acid derivative and member of a new class of compounds called prostones, locally activates ClC-2 Cl(-) channels without activation of prostaglandin receptors. The present study was specifically designed to test and compare lubiprostone and prostaglandin effects at the cellular level using human uterine smooth muscle cells. Effects on [Ca(2+)](i), membrane potential and [cAMP](i) in human uterine smooth muscle cells were measured. 10 nM lubiprostone significantly decreased [Ca(2+)](i) from 188 to 27 nM, which was unaffected by 100 nM SC-51322, a prostaglandin EP receptor antagonist. In contrast 10nM PGE(2) and PGE(1) both increased [Ca(2+)](i) 3-5-fold which was blocked by SC-51322. Similarly, lubiprostone and prostaglandins had opposite/different effects on membrane potential and [cAMP](i). Lubiprostone caused SC-51322-insensitive membrane hyperpolarization and no effect on [cAMP](i). PGE(2) and PGE(1) both caused SC-51322-sensitive membrane depolarization and increased [cAMP](i). Lubiprostone has fundamentally different cellular effects from prostaglandins that are not mediated by EP receptors.

  13. DIVERSITY OF ARSENIC METABOLISM IN CULTURED HUMAN CANCER CELL LINES

    Science.gov (United States)

    Diversity of arsenic metabolism in cultured human cancer cell lines. Arsenic has been known to cause a variety of malignancies in human. Pentavalent As (As 5+) is reduced to trivalent As (As3+) which is further methylated by arsenic methyltransferase(s) to monomethylarson...

  14. Glucagon-Like Peptide 1 Recruits Muscle Microvasculature and Improves Insulin?s Metabolic Action in the Presence of Insulin Resistance

    OpenAIRE

    Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J.; Liu, Zhenqi

    2014-01-01

    Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid in...

  15. Exercise with weight loss improves adipose tissue and skeletal muscle markers of fatty acid metabolism in postmenopausal women

    OpenAIRE

    Ortmeyer, Heidi K.; Goldberg, Andrew P.; Ryan, Alice S.

    2017-01-01

    Objective The effects of six-months weight loss (WL) versus aerobic exercise training (AEX)+WL on fat and skeletal muscle markers of fatty acid metabolism were determined in normal (NGT) and impaired (IGT) glucose tolerant African-American and Caucasian postmenopausal women with overweight/obesity. Methods Fat (gluteal and abdominal) lipoprotein lipase (LPL), and skeletal muscle LPL, acyl-CoA synthase (ACS), β-hydroxacyl-CoA dehydrogenase, carnitine palmitoyltransferase (CPT-1), and citrate s...

  16. Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine

    OpenAIRE

    Ferraro, Elisabetta; Pin, Fabrizio; Gorini, Stefania; Pontecorvo, Laura; Ferri, Alberto; Mollace, Vincenzo; Costelli, Paola; Rosano, Giuseppe

    2016-01-01

    Abstract Background The loss of muscle mass (sarcopenia) and the associated reduced muscle strength are key limiting factors for elderly people's quality of life. Improving muscle performance does not necessarily correlate with increasing muscle mass. In fact, particularly in the elderly, the main explanation for muscle weakness is a reduction of muscle quality rather than a loss of muscle mass, and the main goal to be achieved is to increase muscle strength. The effectiveness of Trimetazidin...

  17. Chronic endocannabinoid system stimulation induces muscle macrophage and lipid accumulation in type 2 diabetic mice independently of metabolic endotoxaemia.

    Directory of Open Access Journals (Sweden)

    Lucie Geurts

    Full Text Available Obesity and type 2 diabetes are characterised by low-grade inflammation, metabolic endotoxaemia (i.e., increased plasma lipopolysaccharides [LPS] levels and altered endocannabinoid (eCB-system tone. The aim of this study was to decipher the specific role of eCB-system stimulation or metabolic endotoxaemia in the onset of glucose intolerance, metabolic inflammation and altered lipid metabolism.Mice were treated with either a cannabinoid (CB receptor agonist (HU210 or low-dose LPS using subcutaneous mini-pumps for 6 weeks. After 3 weeks of the treatment under control (CT diet, one-half of each group of mice were challenged with a high fat (HF diet for the following 3-week period.Under basal conditions (control diet, chronic CB receptor agonist treatment (i.e., 6 weeks induced glucose intolerance, stimulated metabolic endotoxaemia, and increased macrophage infiltration (CD11c and F4/80 expression in the muscles; this phenomenon was associated with an altered lipid metabolism (increased PGC-1α expression and decreased CPT-1b expression in this tissue. Chronic LPS treatment tended to increase the body weight and fat mass, with minor effects on the other metabolic parameters. Challenging mice with an HF diet following pre-treatment with the CB agonist exacerbated the HF diet-induced glucose intolerance, the muscle macrophage infiltration and the muscle's lipid content without affecting the body weight or the fat mass.Chronic CB receptor stimulation under basal conditions induces glucose intolerance, stimulates metabolic inflammation and alters lipid metabolism in the muscles. These effects worsen following the concomitant ingestion of an HF diet. Here, we highlight the central roles played by the eCB system and LPS in the pathophysiology of several hallmarks of obesity and type 2 diabetes.

  18. Delineation of motoneuron subgroups supplying individual eye muscles in the human oculomotor nucleus

    OpenAIRE

    Che Ngwa, Emmanuel; Zeeh, Christina; Messoudi, Ahmed; Büttner-Ennever, Jean A.; Horn, Anja K. E.

    2014-01-01

    The oculomotor nucleus (nIII) contains the motoneurons of medial, inferior, and superior recti (MR, IR, and SR), inferior oblique (IO), and levator palpebrae (LP) muscles. The delineation of motoneuron subgroups for each muscle is well-known in monkey, but not in human. We studied the transmitter inputs to human nIII and the trochlear nucleus (nIV), which innervates the superior oblique muscle (SO), to outline individual motoneuron subgroups. Parallel series of sections from human brainstems ...

  19. Delineation of motoneuron subgroups supplying individual eye muscles in the human oculomotor nucleus

    OpenAIRE

    Emmanuel eChe-Ngwa; Christina eZeeh; Christina eZeeh; Ahmed eMessoudi; Jean Alice Büttner-Ennever; Anja Kerstin Ellen Horn; Anja Kerstin Ellen Horn

    2014-01-01

    The oculomotor nucleus (nIII) contains the motoneurons of medial, inferior and superior recti (MR, IR, SR), inferior oblique (IO) and levator palpebrae (LP) muscles. The delineation of motoneuron subgroups for each muscle is well-known in monkey, but not in human. We studied the transmitter inputs to human nIII and the trochlear nucleus (nIV), which innervates the superior oblique muscle (SO), to outline individual motoneuron subgroups. Parallel series of sections from human brainstems were i...

  20. Skeletal muscle increases FGF21 expression in mitochondrial disorders to compensate for energy metabolic insufficiency by activating the mTOR-YY1-PGC1α pathway.

    Science.gov (United States)

    Ji, Kunqian; Zheng, Jinfan; Lv, Jingwei; Xu, Jingwen; Ji, Xinbo; Luo, Yue-Bei; Li, Wei; Zhao, Yuying; Yan, Chuanzhu

    2015-07-01

    Fibroblast growth factor 21 (FGF21) is a growth factor with pleiotropic effects on regulating lipid and glucose metabolism. Its expression is increased in skeletal muscle of mice and humans with mitochondrial disorders. However, the effects of FGF21 on skeletal muscle in response to mitochondrial respiratory chain deficiency are largely unknown. Here we demonstrate that the increased expression of FGF21 is a compensatory response to respiratory chain deficiency. The mRNA and protein levels of FGF21 were robustly raised in skeletal muscle from patients with mitochondrial myopathy or MELAS. The mammalian target of rapamycin (mTOR) phosphorylation levels and its downstream targets, Yin Yang 1 (YY1) and peroxisome proliferator-activated receptor γ, coactivator 1α (PGC-1α), were increased by FGF21 treatment in C2C12 myoblasts. Activation of the mTOR-YY1-PGC1α pathway by FGF21 in myoblasts regulated energy homeostasis as demonstrated by significant increases in intracellular ATP synthesis, oxygen consumption rate, activity of citrate synthase, glycolysis, mitochondrial DNA copy number, and induction of the expression of key energy metabolic genes. The effects of FGF21 on mitochondrial function required phosphoinositide 3-kinase (PI3K), which activates mTOR. Inhibition of PI3K, mTOR, YY1, and PGC-1α activities attenuated the stimulating effects of FGF21 on intracellular ATP levels and mitochondrial gene expression. Our findings revealed that mitochondrial respiratory chain deficiency elicited a compensatory response in skeletal muscle by increasing the FGF21 expression leve